KR101812357B1 - Pyrrolopyrimidine compounds as inhibitors of cdk4/6 - Google Patents

Abstract

상기 식에서, R¹, R^2Y, R⁴, R⁸-R¹¹, A 및 L은 본원에 정의되어 있다.The present invention relates to novel pyrrolopyrimidine compounds of the general formula (I) and salts, such as the pharmaceutically acceptable salts thereof. The compounds of the present invention are CDK4 / 6 inhibitors and are useful for the treatment of diseases and disorders mediated by CDK4 / 6, such as cancer, such as mantle cell lymphoma, liposarcoma, non-small cell lung cancer, melanoma, squamous cell esophageal cancer and breast cancer . The invention also relates to a pharmaceutical composition comprising a compound of the invention. The invention also relates to a method of inhibiting CDK4 / 6 activity and the treatment of disorders associated therewith, using a pharmaceutical composition comprising a compound of the invention or a compound of the invention.
(I)

In this formula, R ¹ , R ^2Y , R ⁴ , R ⁸ -R ¹¹ , A and L are defined herein.

Description

PYRROLOPYRIMIDINE COMPOUNDS AS INHIBITORS OF CDK4 / 6 < RTI ID = 0.0 >

The present invention relates to novel pyrrolopyrimidine compounds and pharmaceutical compositions thereof, in particular pyrrolopyrimidine compounds which are inhibitors of CDK4 / 6 and pharmaceutical compositions thereof. The present invention also relates to the use of these compounds and compositions in the treatment of hyperproliferative disorders such as cancer.

Mammalian cell cycle progression is a tightly controlled process in which transitions across the various groups are performed in a highly ordered fashion and are protected by multiple checkpoints. Retinoblastoma protein (pRb) is a checkpoint protein for G1 → S transition. pRb associates with a family of E2F transcription factors to prevent its activity in the absence of proper growth stimulation (Ortega et al., Biochimica et Biophysica Acta-Reviews on Cancer 2002; 1602 (1): 73-87; Shapiro, Journal of Clinical Oncology 2006; 24 (11): 1770-1783). Upon mitogen stimulation, the dormant cells initiate entry into its S phase by newly synthesizing D-cyclin, an activator of cyclin-dependent kinases 4 and 6 (CDK4 / 6). Once bound by cyclin, CDK4 / 6 inactivates the pRb protein through phosphorylation. Phosphorylation of pRb releases E2F, directing the transcription of the gene necessary for the S phase. Complete deactivation of pRb requires phosphorylation by both Cyclin D-CDK4 / 6 and Cyclin E-CDK2. CDK4 / 6 phosphorylation at specific sites of pRb (Ser780, Ser795) has been shown to be a prerequisite for cyclin E-CDK2 phosphorylation (Lundberg et al., Molecular and Cellular Biology 1998; 18 (2): 753-761). In addition to D-cyclin, the activity of CDK4 / 6 is regulated by p16 (encoded by the INK4a gene) which inhibits kinase activity (Kamb et al., Science 1994; 264 (5157): 436-440) Reference). The CIP / KIP protein, an inhibitor of cyclin E-CDK2, also binds to the Cyclin D-CDK4 / 6 complex, which causes additional activation of CDK2 by isolating the CIP / KIP protein away from its target (Sherr et al , Genes & Development 1999; 13 (12): 1501-1512). Thus, cyclin D-CDK4 / 6 is a key enzyme complex that regulates the G1 → S group.

The D-cyclin-CDK4 / 6-INK4a-pRb pathway is universally cut to support cell proliferation in cancer. In most cases (about 80%), cancer maintains functional pRb and increases the activity of CDK4 / 6 kinase using a variety of mechanisms (Ortega et al., Biochimica et Biophysica Acta-Reviews on Cancer 2002; 1602 (1): 73-87; Shapiro, Journal of Clinical Oncology 2006; 24 (11): 1770-1783). In mantle cell lymphoma (MCL), cyclin D1 translocates to the IgH promoter (t11: 14), which causes constitutive expression of the protein leading to activation of CDK4 / 6 (Amin, et al., Archives of Pathology &Amp; Laboratory Medicine 2003; 127 (4): 424-431; Oudat, et al., Modern Pathology 2001; 14 (1): 175A). The potential is observed at > 90% of MCL cases and is considered to be characteristic of the disease. D-Cyclin is also dislocated in 20% of multiple myeloma (Bergsagel et al., Immunological Reviews 2003; 194 (1): 96-104).

In addition to disposition, the amount of D-cyclin present may also be increased by amplification or overexpression, examples of which are shown in squamous cell carcinoma of the esophagus (Jiang, et al., Cancer Research 1992; 52 (10): 2980-2983), and cyclin D1 overexpression in breast cancer (see Arnold et al., Journal of Clinical Oncology 2005). CDK4 / 6 kinase activity can also be increased by amplification of the CDK4 gene itself, and co-amplification of the CDK4 and MDM2 genes is observed in almost all cases of dedifferentiated liposarcoma (Sirvent, et al., American Journal of Surgical Pathology 2007; 31 (10): 1476-1489). Genetic inhibitors of CDK4 / 6 are also frequently inactivated in cancers to achieve CDK4 / 6 activation, examples of which include non-small cell lung cancer, melanoma and pancreatic cancer (Brambilla, et al., Journal of Pathol 1999; 188 (4): 351-360; Cowgill et al., American Journal of Surgery 2003; 186 (3): 279-286; Gazzeri, et al., Oncogene 1998; 16 (4): 497-504; Kamb et al., Science 1994; 264 (5157): 436-440; Ortega et al., Biochimica et Biophysica Acta-Reviews on Cancer 2002; 1602 (1): 73-87).

In addition to the above-described genetic defects directly related to the D-cyclin-CDK4 / 6-INK4a-pRb pathway, the activity of CDK4 / 6 kinase can also be enhanced by tumorigenicity abnormalities of the mitogen pathway that increase D- have. Examples include EGFR amplification in non-small cell lung cancer (NSCLC), activation of K-Ras mutation in pancreatic cancer, V600E B-Raf mutation in melanoma, and PTEN inactivation in colon cancer (Dailey, et al. Garcia-Echeverria, Purinergic Signalling 2009; 5 (1): 117-125, < RTI ID = 0.0 > Oncogene 2009; 28: S14-S23, Sharma, et al., Nature Reviews Cancer 2007; 7 (1) 3): 169-181).

Taken together, a number of human neoplasms achieve enhanced cell proliferation by increasing CDK4 / 6 activity, and small molecule inhibitors of these kinases will provide an effective means of treating the disease.

Inhibitors of CDKs are known and patent applications for such inhibitors have been filed (see, for example, WO 2007/140222).

Thus, attempts have been made to produce compounds that inhibit CDK4 / 6 activity, and a number of such compounds have been disclosed in the art. However, given the number of pathological responses mediated by CDK4 / 6, there is a continuing need for inhibitors of CDK4 / 6 that can be used to treat a variety of conditions, including cancer.

The present invention relates to novel pyrrolopyrimidine compounds of the general formula (I) and salts, such as the pharmaceutically acceptable salts thereof.

(I)

In this formula, R ¹ , R ^2Y , R ⁴ , R ⁸ -R ¹¹ , A and L are defined herein.

The compounds of the present invention are CDK4 / 6 inhibitors and are useful for the treatment of diseases and disorders mediated by CDK4 / 6, such as cancer, such as mantle cell lymphoma, liposarcoma, non-small cell lung cancer, melanoma, squamous cell esophageal cancer and breast cancer . The invention also relates to a pharmaceutical composition comprising a compound of the invention. The invention also relates to a method of inhibiting CDK4 / 6 activity and the treatment of disorders associated therewith, using a pharmaceutical composition comprising a compound of the invention or a compound of the invention.

(I)

In this formula,

R ¹ is C _{3 - 7} alkyl; C _{1 - 7} cycloalkyl _{- 6} C ₄ optionally substituted with 1 substituent selected from the group consisting of alkyl and OH; C _{1 - 6} alkyl, C (CH _{3) 2} CN and with 1 substituent selected from the group consisting of OH, optionally substituted phenyl; Cyclopropyl or C _{1 -} A with 1 substituent selected from the group consisting of _6-alkyl optionally substituted piperidinyl; Cyclopropyl or C _{1 -} A with 1 substituent selected from the group consisting of _6-alkyl, optionally substituted tetrahydropyranyl; Or bicyclo [2.2.1] heptanyl;

A is CH or N;

R ¹¹ is hydrogen or C _{1 - 4} alkyl and;

L is a bond, C (O) or S (O) ₂ ;

R ^2Y is

이고;

ego;

V is NH or CH ₂ ;

X is O or CH ₂ ;

W is O or NH;

m and n are each independently 1, 2 or 3, provided that m and n are not both 3;

Each R ^2Y is hydroxy, NH _2, and -SC _{1 - 3} alkyl, C ₁ each independently optionally substituted with one or two substituents selected from the group consisting of _{- 3} alkyl; CD ₃ ; Halo; Oxo; C _{1 - 3} haloalkyl; Hydroxy; NH ₂ ; Dimethylamino; benzyl; -C (O) -C _1-3 alkyl optionally substituted with one or two substituents each independently selected from the group consisting of NH ₂ , -SCH ₃ and NHC (O) CH ₃ ; _{-S (O) 2 -C 1 -} 4 alkyl; Pyrrolidinyl-C (O) -; And -C (O) ₂ -C _{1 -} is optionally substituted with 1 to 4 substituents each selected independently from the group consisting of _3-alkyl;

R ⁴ is hydrogen, deuterium or C (R ⁵ ) (R ⁶ ) (R ⁷ );

R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently H or deuterium.

One embodiment of the present invention is a compound according to the formula (I-B):

<Formula I-B>

In this formula,

L is a bond or C (O);

R ^2Y is

이고;

ego;

V is NH or CH ₂ ;

X is O or CH ₂ ;

W is O or NH;

m and n are each independently 1, 2 or 3, provided that m and n are not both 3;

Each R ^2Y is hydroxy, NH _2, and -SC _{1 - 3} alkyl, C ₁ each independently optionally substituted with one or two substituents selected from the group consisting of _{- 3} alkyl; CD ₃ ; C _{1 - 3} haloalkyl; Hydroxy; NH ₂ ; Dimethylamino; benzyl; -C (O) -C _1-3 alkyl optionally substituted with one or two substituents each independently selected from the group consisting of NH ₂ , -SCH ₃ and NHC (O) CH ₃ ; _{-S (O) 2 -C 1 -} 4 alkyl; Pyrrolidinyl-C (O) -; And -C (O) ₂ -C _{1 -} is optionally substituted with 1 to 4 substituents each selected independently from the group consisting of _3-alkyl;

R ¹ , R ⁴ -R ¹¹ and A are as defined in formula (I) above.

Another embodiment of the present invention is a compound according to the formula (I-C):

&Lt; EMI ID =

In this formula,

R ¹ is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl optionally substituted with ^one of methyl, ethyl or OH;

A is CH or N;

L is a bond, -C (O) - or S (O) ₂ -;

R ^2Y is

이고;

ego;

Wherein each R ^2Y is optionally substituted with 1 or 2 substituents independently selected from halogen, methyl, ethyl or oxo;

V is NH or CH ₂ ; R ⁴ is hydrogen, deuterium or C (R ⁵ ) (R ⁶ ) (R ⁷ ); R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently H or deuterium.

In one embodiment of the present invention, L is a bond. In another embodiment, L is C (O).

In one embodiment, A is CH. In another embodiment, A is N. Preferably, A is CH.

Preferably, R &lt; ¹¹ &gt; is hydrogen or methyl. Hydrogen is most preferred.

Preferably, R ⁴ is C (R ⁵ ) (R ⁶ ) (R ⁷ ), and R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are hydrogen.

Preferably, R ¹ is one of C _{1 - 7} is cycloalkyl _- C ₄ alkyl optionally substituted with a _6. In a more preferred embodiment, R &lt; ^{1 &gt;} is optionally substituted cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cyclopentyl is most preferred. Unsubstituted cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl are also preferred.

In another embodiment of the present invention, R &lt; ^2Y &gt; is

이다.

to be.

In another embodiment, R &lt; ^2Y &gt; is

이다.

to be.

In another embodiment, R &lt; ^2Y &gt; is

이다.

to be.

이다.In another embodiment, R &lt; ^2Y &gt; is

to be.

이다.In another embodiment, R &lt; ^2Y &gt; is

to be.

이다.In another embodiment, R &lt; ^2Y &gt; is

to be.

이다.In another embodiment, R &lt; ^2Y &gt; is

to be.

이다.In another embodiment, R &lt; ^2Y &gt; is

to be.

이다.In a preferred embodiment, R ^2Y is

to be.

이다.In a preferred embodiment, R ^2Y is one C _{1 - 3} alkyl optionally substituted with

to be.

이다.In a preferred embodiment, R ^2Y is one C _{1 - 3} alkyl optionally substituted with

to be.

이다.In a preferred embodiment, R ^2Y is

to be.

이다.In a preferred embodiment, R ^2Y is one C _{1 - 3} alkyl optionally substituted with

to be.

이다.In a preferred embodiment, R ^2Y is one C _{1 - 3} alkyl optionally substituted with

to be.

이다.In a preferred embodiment, R ^2Y is

to be.

이다.In a preferred embodiment, R ^2Y is

to be.

Preferably, R ^2Y is unsubstituted.

Specific compounds of the present invention include:

Synthesis of cyclopentyl-2- (5- (9-hydroxy-1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] , N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide;

Cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-aza- lt; / RTI &gt; d] pyrimidine-6-carboxamide;

(3, 8-diaza-bicyclo [3.2.1] octane-3-carbonyl) -pyridin-2- ylamino] -7H- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide;

Synthesis of 7-cyclopentyl-2- [5- (4-oxo-3,9-diaza-bicyclo [4.2.1] non-3-yl) -pyridin- 2-ylamino] -7H- pyrrolo [ , 3-d] pyrimidine-6-carboxylic acid dimethylamide;

Synthesis of 7-cyclopentyl-2- [5- ((lR, 6S) -4-oxo-3,9-diaza-bicyclo [4.2.1] 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide;

2-ylamino] -7H-pyrrolo [2,3-c] pyridin-2- d] pyrimidine-6-carboxylic acid dimethylamide;

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- d] pyrimidine-6-carboxylic acid dimethylamide;

2-ylamino] -7H-pyrrolo [2,3-c] pyridin-2- d] pyrimidine-6-carboxylic acid dimethylamide;

Pyridin-2-ylamino) -7-cycloheptyl-N, N-dimethyl-7H-pyrrolo [2,3 lt; / RTI &gt; d] pyrimidine-6-carboxamide;

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- 2,3-d] pyrimidine-6-carboxylic acid dimethylamide;

Synthesis of 7-cyclopentyl-2- [5 - ((S, S) -2,5-diaza-bicyclo [2.2.1] heptane- 2- carbonyl) -pyridin- Lt; / RTI &gt; [2,3-d] pyrimidine-6-carboxylic acid methylamide;

3-carbonyl) -pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidin- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide;

Diazabicyclo [3.3.1] nonane-9-carbonyl) pyridin-2-ylamino) -7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide;

2- [5- (3,8-diaza-bicyclo [3.2.1] octane-8-carbonyl) -pyridin-2-yl Amino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide;

Synthesis of 7-cyclopentyl-2- [5 - ((1S, 6R) -3,9-diaza-bicyclo [4.2.1] Lt; / RTI &gt; [2,3-d] pyrimidine-6-carboxylic acid dimethylamide;

Synthesis of 7-cyclopentyl-2- [5 - ((1R, 6S) -3,9-diaza-bicyclo [4.2.1] Lt; / RTI &gt; [2,3-d] pyrimidine-6-carboxylic acid dimethylamide;

2-ylamino] -7H-pyrrolo [2,3-c] pyridin-2- d] pyrimidine-6-carboxylic acid dimethylamide;

Pyrrolo [2,3-d] pyrimidin-2-yl] -pyridin- Pyrimidine-6-carboxylic acid dimethylamide;

Cyclopentyl-N, N-dimethyl-2- (5- (5'-oxo-8-azaspiro [bicyclo [3.2.1] octane-3,3'-pyrrolidin] ) Pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide;

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- d] pyrimidine-6-carboxylic acid dimethylamide;

Synthesis of 7-cyclopentyl-N, N-dimethyl-2- (5- (2-oxo-1-oxa-3,8-diazaspiro [4.5] decan- -Pyrrolo [2,3-d] pyrimidine-6-carboxamide;

Synthesis of 7-cyclopentyl-2- [5 - ((lS, 6R) -4-oxo-3,9-diaza-bicyclo [ 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide;

Pyridin-2-ylamino] -7-phenyl-7H-pyrrolo [2,3- 3-d] pyrimidine-6-carboxylic acid dimethylamide; And

(4-oxo-3,9-diazabicyclo [4.2.1] nonan-3-yl) pyridin-2-ylamino) -7H-pyrrolo [ 2,3-d] pyrimidine-6-carboxamide &lt; / RTI &gt;

Preferred compounds of the present invention include those selected from the group consisting of:

2-ylamino] -7H-pyrrolo [2,3-c] pyridin-2- d] pyrimidine-6-carboxylic acid dimethylamide;

Synthesis of 7-cyclopentyl-2- [5 - ((S, S) -2,5-diaza-bicyclo [2.2.1] heptane- 2- carbonyl) -pyridin- Lt; / RTI &gt; [2,3-d] pyrimidine-6-carboxylic acid dimethylamide;

Synthesis of 7-cyclopentyl-2- [5- ((lR, 6S) -4-oxo-3,9-diaza-bicyclo [4.2.1] 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide;

Synthesis of 7-cyclopentyl-2- [5 - ((1S, 5S) -3,6-diaza-bicyclo [3.2.1] octane- 3-carbonyl) -pyridin- Lt; / RTI &gt; [2,3-d] pyrimidine-6-carboxylic acid dimethylamide;

Yl) -pyridin-2-ylamino] - (4-fluorobenzyl) -2,3-dihydro- 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide;

4-oxo-3,9-diaza-bicyclo [4.2.1] non-3-yl) -pyridin- 2- ylamino] - 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide;

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- 2,3-d] pyrimidine-6-carboxylic acid dimethylamide;

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- 2,3-d] pyrimidine-6-carboxylic acid dimethylamide;

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- d] pyrimidine-6-carboxylic acid dimethylamide;

Synthesis of 7-cyclopentyl-N, N-dimethyl-2- (5- (3-oxo-1,4-diazabicyclo [3.2.2] Lt; / RTI &gt; [2,3-d] pyrimidine-6-carboxamide; And

Synthesis of 7-cyclopentyl-N, N-dimethyl-2- (5 - ((1R, 6S) -9- Ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide.

Preferred compounds of the present invention include those selected from the group consisting of:

Pyrrol-2 (1H) -yl) pyridin-2-ylmethyl] -2- (5 - ((3aS, 6aR) -oxohexahydropyrrolo [3,4- Ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide;

Pyrrol-2 (1H) -yl) pyridin-2-ylmethyl] -2- (5 - ((3aR, 6aS) Ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide;

(6H, 7H, 7aH) -yl) pyridine prepared in Step 1 of Example 1 was used in the same manner as in Reference Example 1, except that 7-cycloheptyl-N, N-dimethyl- -2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide;

Pyridin-5 (6H, 7H, 7aH) -yl) pyridine prepared in Step 1 of Example 1 was used instead of 4- -2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide;

Pyridin-5 (6H, 7H, 7aH) -yl) pyridine prepared in Step 1 of Example 1 was used instead of 4- -2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide; And

3,4-c] pyrrol-2 (1H) -yl) -5-methyl-1-oxohexahydro pyrrolo [3,4- Pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide.

Preferred compounds of the present invention include those selected from the group consisting of:

N, N-dimethyl-2- (5 - ((1R, 3R, 5S) -2 '-oxo-8- azaspiro [bicyclo [3.2.1] octane- Pyridin-3-yl) pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide;

N-dimethyl-2- (5- (2-oxo-1-oxa-3,8-diazaspiro [4.6] undecan-3- yl) pyridin- 7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide;

Synthesis of 7-cyclopentyl-N, N-dimethyl-2- (5- (2-oxo-1-oxa-3,7-diazaspiro [4.5] decan- -Pyrrolo [2,3-d] pyrimidine-6-carboxamide;

7-diaza-spiro [4.5] dec-3-yl) -pyridin-2-ylamino] -7H -Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide; And

4-yl) -pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidin- -Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Terms and Definitions

The term "alkyl" has 1 to 6 carbon atoms as used herein, (C _{1 - 6} alkyl), 3 to 7 carbon atoms (C _3-7 alkyl), 1 to 4 carbon atoms (C _{1 - 4} alkyl) or 1 to 3 carbon _atoms having a completely saturated minutes (C _{1 3} alkyl) refers to a branched or unbranched hydrocarbon moiety. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, Butyl, 3,3-dimethylpropyl, hexyl, 2-methylpentyl, and the like.

The term "cycloalkyl" as used herein refers to a partially or fully hydrogenated nonaromatic carbocyclic ring and may exist as a single ring, a bicyclic ring, a tricyclic ring or a spiral ring. Unless otherwise indicated, cycloalkyl refers to cyclic hydrocarbon groups of 3-14 carbon atoms. Cycloalkyl groups also refer to cyclic hydrocarbon groups having from 3 to 9 ring carbon atoms or from 4 to 7 ring carbon atoms. Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and the like. Exemplary bicyclic hydrocarbon groups include but are not limited to boronyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.1 ] Heptenyl, 6,6-dimethylbicyclo [3.1.1] heptyl, 2,6,6-trimethylbicyclo [3.1.1] heptyl, bicyclo [2.2.2] octyl and the like. Exemplary tricyclic hydrocarbon groups include adamantyl and the like.

"Deuterium" or "D" or "d" refers to isotopes of hydrogen whose nuclei contain one proton and one neutron. It is understood that when a particular location is designated as having deuterium, the amount of deuterium present at that location is greater than the natural abundance of deuterium (typically 0.015%). Unless otherwise indicated, where the position is specifically designated as "D" or "deuterium ", it is understood that the position has deuterium in abundance greater than the natural abundance of deuterium.

The term " halogen "or" halo " as used herein refers to fluoro, chloro, bromo and iodo.

The term "haloalkyl" as used herein refers to an alkyl group in which at least one hydrogen atom attached to the carbon atom of the alkyl group is replaced by halo, preferably fluoro. Examples of haloalkyl groups are mono-, di- and tri-fluoromethyl, mono-, di- and tri-chloromethyl, mono-, di-, tri-, tetra- and penta-fluoroethyl, Di-, tri-, tetra- and penta-chloroethyl.

The term "optionally substituted " as used herein means that groups such as alkyl, cycloalkyl, or certain R groups may be unsubstituted or substituted with one or more substituents as defined herein. The term "substituted" in reference to a group indicates that a hydrogen atom attached to an atom in the group is replaced. The term "substituted" means that such substitution is made according to the atom to which it is substituted and the valency permitted for the substituent, and that the compound with stable substitution (i.e., does not spontaneously undergo transformation such as by rearrangement, cyclization or elimination) And the like. In certain embodiments, a single atom may be substituted with more than one substituent as long as the substitution is made according to the accepted valence of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group.

The term "compounds of the present invention" refers to the compounds of formula (I) and the salts thereof, such as the pharmaceutically acceptable salts of such compounds, as well as all stereoisomers (including diastereomers and enantiomers) Refers to tautomeric and isotopically labeled compounds. Solvates and hydrates are generally regarded as pharmaceutical compositions of the compounds of the present invention.

The symbols and rules used in these procedures, reactions and examples used herein are consistent with those used in the latest scientific literature (e.g., Journal of the American Chemical Society or Journal of Biological Chemistry) . Unless otherwise indicated, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification.

ACN acetonitrile

AcOH acetic acid

aq. Mercury

BnBr benzyl bromide

boc tert-Butoxycarbonyl

C Celsius

cat. Amount of catalyst

CDI Carbonyldiimidazole

CSA camphorsulfonic acid

conc. thick

Cs ₂ CO ₃ Cesium carbonate

Da Dalton

degrees

DIBAL, DIBAL-H Diisobutylaluminum hydride

DIPEA Diisopropylethylamine

DIPC N, N'-diisopropylcarbodiimide

DMF N, N-dimethylformamide

DMI 1,3-dimethyl-2-imidazolidinone

DMP Des-Martin Fear Iodine

DCC N, N-dicyclohexylcarbodiimide

DCE dichloroethane

DCM dichloromethane

DMAP 4-Dimethylaminopyridine

DMSO dimethylsulfoxide

EtOAc ethyl acetate

EtOH Ethanol

eq equivalent

g gas

h Time

HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate

HMPA hexamethylphosphoramide

hep heptane

HCl hydrochloric acid

inh. control

imid. Imidazole

K Kelvin

KHMDS Potassium hexamethyldisilyl azide

K ₂ CO ₃ Potassium carbonate

LDA Lithium diisopropylamine

LiBH ₄ lithium borohydride

LHMDS Lithium hexamethyldisilyl azide

LC liquid chromatography

LC / MS liquid chromatography mass spectrum

M Mall

MeCN acetonitrile

MeOH Methanol

MgSO ₄ magnesium sulfate

MHz megahertz

min min

mol.

NaBH ₄ Sodium borohydride

N-Norm

NMR nuclear magnetic resonance

Pd / C palladium on carbon

PEG (750) O- (2-aminoethyl) -O ' -methyl polyethylene glycol 750; NH ₂ (CH ₂ CH ₂ O) _n CH ₃ ; CAS # [80506-64-5]; Fluka 07964; Average MW = 750

PS polystyrene

Py pyridine

PPM million

RP reverse phase

RT room temperature

R _t retention time

s solids

satd. saturation

TBS tert-butyldimethylsilyl

TMS trimethylsilyl

TBAF tetrabutylammonium fluoride

TBTU O-Benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate

TLC thin layer chromatography

TEA triethylamine

TFA Trifluoroacetic acid

THF tetrahydrofuran

h Time

min min

m / z mass versus charge

MS mass spectrum

NMR nuclear magnetic resonance

One of ordinary skill in the art will appreciate that salts of the compounds of formula I, such as pharmaceutically acceptable salts, may be prepared. The term "salt" or "salts" as used herein refers to an acid addition salt or a base addition salt of a compound of the present invention. The term " pharmaceutically acceptable salts "refers to those salts which possess the biological effectiveness and properties of the compounds of this invention, and are typically not biologically or otherwise undesirable. Accordingly, the present invention also relates to salts, preferably pharmaceutically acceptable salts, of the compounds of formula (I).

Pharmaceutically acceptable acid addition salts may be formed with inorganic and organic acids and include, for example, acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, / Sulfate, camphorsulfonate, chloride / hydrochloride, chlortheophilonate, citrate, ethanedisulfonate, fumarate, glusceptate, gluconate, glucuronate, hydrate, hydroiodide / Maleate, maleate, mandelate, mesylate, methylsulfate, naphthoate, salicylate, nicotinate, maleate, maleate, isoleucine, Nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogenphosphate Byte, the acetate salt as a poly-galacturonic a carbonate, propionate, stearate, succinate, alcohol uposatha florisil rate, tartrate, tosylate and trifluoroacetate.

The inorganic acid from which the salt can be derived includes, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.

The organic acid from which the salt can be derived is selected from the group consisting of, for example, acetic, propionic, glycolic, oxalic, maleic, malonic, succinic, fumaric, tartaric, citric, benzoic, mandelic, methanesulfonic, ethanesulfonic, Salicylic acid, and the like.

Pharmaceutically acceptable base addition salts may be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; Particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Particular organic amines include isopropylamine, benzathine, colinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention may be synthesized from parent compounds, basic or acidic moieties by conventional chemical methods. Generally, such salts are prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (e.g., Na, Ca, Mg or K hydroxide, carbonate, bicarbonate, etc.) Can be prepared by reacting the free base form of the compound with a stoichiometric amount of the appropriate acid. This reaction is typically carried out in water or an organic solvent, or a mixture of both. In general, the use of a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred when feasible. A list of additional suitable salts is found, for example, in Remington &apos; s Pharmaceutical Sciences, 20th ed., Mack Publishing Company, Easton, Pa., (1985); And "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

The compounds according to formula I may contain one or more asymmetric centers (also referred to as chiral centers) and may therefore exist as individual enantiomers, diastereomers or other stereoisomeric forms, or mixtures thereof. A chiral center, such as a chiral carbon atom, may also be present in a substituent, such as an alkyl group. In the case where the stereochemistry of the chiral centers present in Formula I, or any of the chemical structures exemplified herein, is not specified, the structure is intended to include any stereoisomer or mixture thereof. Thus, compounds according to formula (I) containing one or more chiral centers can be used as racemic mixtures, enantiomerically enriched mixtures or enantiomerically pure individual stereoisomers.

As used herein, the term "isomer" refers to different compounds that have the same molecular formula but differ in the arrangement and coordination of the atoms. The term " optical isomer "or" stereoisomer ", as used herein, refers to any of a variety of stereoisomeric coordinates that may exist for a given compound of the invention and includes geometric isomers. It is understood that the substituent may be attached to the chiral center of the carbon atom. Accordingly, the present invention encompasses enantiomers, diastereoisomers, or racemates of compounds. An "enantiomer" is a pair of mirror stereoisomers that are not overlapping with each other. A 1: 1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, this term is used to denote a racemic mixture. "Diastereoisomers" are stereoisomers that have two or more asymmetric atoms but are not mirror images of one another. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. If the compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by R or S. When the chemical structure of a compound or substituent is shown, the stereochemistry may also be specified using thick wedge bonds or hatching lines. Subdivided compounds whose absolute sequence is not revealed can be represented by (+) or (-) (preferential or left-sided) depending on the direction in which they rotate the plane polarized light at the wavelength of the sodium D line. Certain of the specific compounds described herein contain one or more asymmetric centers or axes and thus may have other stereoisomeric forms which may be defined as (R) - or (S) - in terms of enantiomers, diastereomers, and absolute stereochemistry Can be generated. The present invention is intended to include all such possible isomers, such as racemic mixtures, optically pure forms, and intermediate mixtures.

The optically active (R) - and (S) -isomers may be prepared using chiral synthesis units or chiral reagents, or may be resolved using conventional techniques. Any resulting racemates of the final products or intermediates can be separated by known methods, for example by separation of their diastereomeric salts, into optical isomers obtained by optically active acids or bases, and optically active acidic or basic The compound can be liberated. In particular, by using the basic moiety thus, the compounds of the present invention can be reacted with an optically active acid such as, for example, tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O, O'-p-toluoyltartaric acid, Or by fractional crystallization of the salt formed by the acid, the acid, the acid, the acid, the acid, the acid, the acid or the camphor-10-sulfonic acid. The racemic product can also be resolved by chiral chromatography using, for example, high pressure liquid chromatography (HPLC) using a chiral adsorbent.

When the compound of the present invention contains a double bond, the substituent may be an E or Z coordination. When the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-coordination. It is also intended to include all tautomeric forms.

Any asymmetric atoms (e.g., carbon, etc.) of the compound (s) of the present invention may be enriched in racemic or enantiomerically enriched form, for example, (R) -, (S) - It can exist as a coordination. In certain embodiments, each asymmetric atom has an enantiomeric excess of at least 50%, an enantiomeric excess of at least 60%, an enantiomeric excess of at least 70%, an enantiomeric excess of at least 80% in the (R) - or (S) An enantiomeric excess of at least 90%, an enantiomeric excess of at least 95%, or an enantiomeric excess of at least 99%. Substituents at an atom having an unsaturated bond may be present in the cis- (Z) - or trans- (E) - form, if possible.

Any resulting isomeric mixtures can be separated into pure or substantially pure geometric or optical isomers, diastereoisomers, racemates, for example, by chromatography and / or fractional crystallization based on the physico-chemical differences of the constituents .

Substitution with heavier isotopes, in particular deuterium (i.e., ² H or D), provides for greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements or certain therapeutic advantages from the improvement of therapeutic index . In this regard, it is understood that deuterium is considered as a substituent of the compounds of the present invention. The concentration of this heavier isotope, especially deuterium, can be defined by the isotope enrichment factor. The term "isotope enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. In the case where the substituents in the compounds of the present invention are indicated deuterium, these compounds are present in an amount of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), 4000 (60% deuterium incorporation), 4500 (95% deuterium incorporation), more than 6,500 (90% deuterium incorporation), more than 5,000 (75% deuterium incorporation) (99% deuterium incorporation), or 6633.3 or more (99.5% deuterium incorporation).

In addition to the currently exemplified deuterium-containing compounds, any of the formulas given herein are also intended to represent the unlabeled form of the compound, as well as the isotope labeled form. An isotopically labeled compound has the structure depicted by the formula given herein except that at least one atom is replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include hydrogen, isotopes of carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, for example, each ^{2 H, 3 H, 11 C} , 13 C, 14 C, 15 N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl, ¹²⁵ I. The present invention includes compounds in which various isotopically labeled compounds, such as radioactive isotopes such as ³ H, ¹³ C and ¹⁴ C, are present as defined herein. Such isotope labeled compounds may be used in a variety of biological applications including, but not limited to, metabolic studies (using ¹⁴ C), reaction kinetics studies (e.g. using ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) (SPECT) (including drug or substrate tissue distribution assays), or in radiotherapy of patients. In particular, ¹⁸ F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the invention and prodrugs thereof can be prepared by replacing the isotope unlabeled reagents with readily available isotopically labeled reagents by performing the procedures described in the reaction schemes described below or the Examples and Preparations can do.

The isotopically-labeled compounds of the invention are generally prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the appended examples and preparation of compounds, using appropriate equivalents instead of the non- Can be prepared using element-labeled reagents.

In addition, the compounds of the present invention (including salts thereof) may also be obtained in the form of their hydrates, or may include other solvents used for their crystallization. The compounds of the present invention may form solvates, either physically or by design, with a pharmaceutically acceptable solvent (including water); Thus, the present invention is intended to include both solvated and unsolvated forms. The term "solvate" refers to a molecular complex with one or more solvent molecules of a compound of the invention (including a pharmaceutically acceptable salt thereof). Such solvent molecules are those conventionally used in the pharmaceutical industry, such as water, ethanol, etc., which are known to be harmless to the recipient. The term "hydrate" refers to a complex in which the solvent molecule is water. Include acetone, d ₆ -DMSO - In addition, the present invention a pharmaceutically acceptable solvate thereof according to the solvent of crystallization ones which may be substituted with isotope, for example D ₂ O, d _6.

The present invention also provides prodrugs of the compounds of the present invention which are converted in vivo to the compounds of the present invention. Prodrugs are active or inert compounds that are chemically modified with the compounds of the present invention through in vivo physiology, such as hydrolysis, metabolism, etc., after administration of the prodrug to the subject. The suitability and techniques associated with the manufacture and use of prodrugs are well known to those skilled in the art. Prodrugs can be conceptually classified into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs. The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic Press, San Diego, Calif., 2001). Generally, a bioprecursor precursor drug is a compound that is inert or has a lower activity than the corresponding active drug compound, contains one or more protecting groups and is converted to the active form by metabolism or solvolysis. Both the active drug form and any released metabolite should have acceptable low toxicity.

The carrier prodrug is a drug compound that improves absorption and / or local delivery to a drug compound containing the transport moiety, e. G., The site (s) of action. In such carrier prodrugs, the linkage between the drug moiety and the transport moiety is a covalent bond, the prodrug is inert or is less active than the drug compound, and any released transport moiety is an acceptably non-toxic . For prodrugs intended to enhance uptake of the transport moiety, the release of the transport moiety typically must be rapid. In other cases, it is preferred to use moieties that provide sustained release, e.g., certain polymers or other moieties such as cyclodextrins. The carrier prodrug can be used, for example, to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effect, increased site-specificity, reduced toxicity and adverse reaction, and / or Improvement of drug formulations (e.g., inhibition of stability, water solubility, undesirable sensory receptivity or physicochemical properties). For example, the lipophilic group may be formed by (a) a hydroxyl group and a lipophilic carboxylic acid (for example, a carboxylic acid having at least one lipophilic moiety) or (b) a carboxylic acid group and an oleophilic alcohol For example, alcohols having one or more lipophilic moieties, such as aliphatic alcohols.

Exemplary prodrugs are, for example, esters of free carboxylic acids and S-acyl derivatives of thiols and O-acyl derivatives of alcohols or phenols, wherein acyl has the meanings as defined herein. Suitable prodrugs are often pharmaceutically acceptable ester derivatives that can be converted to the carboxylic acid by solvolysis under physiological conditions, such as lower alkyl esters, cycloalkyl esters, lower alcohols, Mono- or disubstituted lower alkyl esters such as □ - (amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl) -lower alkyl esters, □ - (lower alkanoyloxy, Lower alkoxycarbonyl or di-lower alkylaminocarbonyl) -lower alkyl esters such as pivaloyloxymethyl esters and the like. Also, the amine is shielded in vivo as an arylcarbonyloxymethyl-substituted derivative which is cleaved by an esterase to release a free drug and formaldehyde (Bundgaard, J. Med. Chem. 2503 (1989) . In addition, drugs containing acidic NH groups such as imidazole, imide, indole, etc. are blocked with N-acyloxymethyl groups (Bundgaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups are shielded as esters and ethers. EP 039,051 (Sloan and Little) discloses Mannich-base hydroxamic acid prodrugs, their preparation and their use.

Composition

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition may be formulated for a particular route of administration, such as oral administration, parenteral administration and rectal administration, and the like. In addition, the pharmaceutical compositions of the present invention may be prepared in solid form, including, but not limited to, capsules, tablets, pills, granules, powders or suppositories, or liquid forms, including, but not limited to, solutions, suspensions or emulsions. The pharmaceutical composition may be applied to conventional pharmaceutical operations such as sterilization and / or may contain conventional inert diluents, lubricants, buffers as well as adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers and buffers.

Typically, the pharmaceutical composition comprises the active ingredient in combination with a) a diluent, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) a lubricant, for example silica, talc, stearic acid, its magnesium or calcium salt and / or polyethylene glycol; C) binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; If necessary d) disintegrants, for example starch, agar, alginic acid or its sodium salt or a foamable mixture; And / or e) tablets or gelatin capsules, which are included with absorbents, colorants, flavors and sweeteners.

Tablets may be film coated or enteric coated according to methods known in the art. Compositions suitable for oral administration comprise an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions, which compositions comprise sweeteners, flavors, colorants, and preservatives to provide a pharmaceutically elegant, &Lt; / RTI &gt; Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulating and disintegrating agents, for example corn starch or alginic acid; Binders, for example starch, gelatin or acacia; And lubricants such as magnesium stearate, stearic acid or talc. Tablets are either uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract thereby providing a longer lasting action. For example, time delay materials such as glyceryl monostearate or glyceryl distearate may be used. Oral formulations may be prepared by mixing the active ingredient in an inert solid diluent, for example hard gelatine capsules mixed with calcium carbonate, calcium phosphate or kaolin, or water or an oil medium, for example peanut oil, liquid paraffin or olive oil, May be provided as a mixed soft gelatin capsule.

Certain compositions that are injectable are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. The composition may be sterilized and / or may contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, solubility enhancers, salts for the control of osmotic pressure and / or buffers. In addition, they may also contain other therapeutically valuable substances. Each of the above compositions is prepared according to conventional mixing, granulating or coating methods and contains about 0.1-75%, or about 1-50% of the active ingredient.

Compositions suitable for transdermal application comprise an effective amount of a compound of the invention together with suitable carriers. Suitable carriers for transdermal delivery include an absorbable pharmacologically acceptable solvent to aid passage through the skin of the host. For example, a transdermal device may include a backing member, a reservoir containing the compound optionally with the carrier, a rate control barrier for delivering the compound to the skin of the host at a predetermined, optionally controlled rate over a prolonged period of time, Gt; a &lt; / RTI &gt; bandage.

For example, compositions suitable for topical application to the skin and eyes include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations for delivery by, for example, aerosols and the like. Such topical delivery systems may be suitable for use in, for example, prophylactic applications, particularly for the treatment of skin, for example skin cancer, such as sun creams, lotions, sprays and the like. Thus, they are particularly suitable for topical use, including cosmetics, formulations, which are well known in the art. These may contain solubilizing agents, stabilizers, thickening agents, buffers and preservatives.

The topical application as used herein may also be for inhalation or intranasal application. This can conveniently be carried out in the form of a dry powder (either alone, as a mixture, for example as a mixture of lactose (for example, lactose), &lt; RTI ID = , Or as a mixed component particle with, for example, a phospholipid).

The present invention also provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as an active ingredient since water can facilitate the degradation of certain compounds. The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low water containing ingredients, and low moisture or low humidity conditions. The anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Thus, by packaging the anhydrous compositions using known materials to prevent exposure to water, they can be included in suitable regulatory kits. Examples of suitable packaging include, but are not limited to, airtight foils, plastics, unit dose containers (e.g. vials), blister packs and strip packs.

The present invention also provides pharmaceutical compositions and dosage forms comprising one or more agonists that reduce the rate at which the compounds of the invention as active ingredients are degraded. Such agents, referred to herein as "stabilizers " include, but are not limited to, antioxidants such as ascorbic acid, pH buffers or salt buffers and the like.

How to use

The compounds of the present invention are inhibitors of CDK4 / 6, and thus it may be possible to treat diseases in which the underlying pathological conditions are mediated (at least in part) by CDK4 / 6. Such diseases include cancer, and other diseases with impaired cell proliferation, apoptosis or differentiation.

Thus, the compounds of the present invention may be useful in the treatment of tumors with RB + ve (retinoblastoma protein positive) tumors, such as Ras, Raf, mutations in growth factor receptors or overexpression of growth factor receptors. The compounds of the present invention may also be useful for the treatment of tumors with amplification of the CDK4 and CDK6 genes, as well as tumors over-expressing the cyclin-dependent kinase cyclin partners. The compounds of the present invention may also be useful in the treatment of RB- and tumors.

The compounds of the present invention may also be useful in the treatment of tumors having gene anomalies that activate CDK4 / 6 kinase activity. These include, but are not limited to, cancers with D-Cyclin potential, such as mantle cell lymphomas and multiple myeloma, cancers with D-cyclin amplification such as breast and squamous cell carcinomas, cancers with CDK4 amplification such as liposarcoma, CDK6 amplification or overexpression But are not limited to, cancers having cancer, such as T-cell lymphoma, and cancers with p16 inactivation, such as melanoma, non-small cell lung cancer, and pancreatic cancer.

The compounds of the present invention may be useful for the treatment of cancers having a gene abnormality in the upstream regulator of D-cyclin, wherein said defect causes an increase in the amount of D-cyclin present, have. These include acute myelogenous leukemia with FLT3 activation, breast cancer with Her2 / neu overexpression, ER dependency or triple negative phenotype, colon cancer with MAPK, PI3K or WNT pathway mutation, melanoma with activation mutation of MAPK pathway, EGFR Non-small cell lung cancer having pathway activation abnormality, and pancreatic cancer having an activation abnormality of the MAPK pathway, including K-ras mutation.

Examples of cancers that can be treated with the compounds of the invention include, but are not limited to, carcinomas such as bladder, breast, colon (e.g., colorectal carcinoma such as colon adenocarcinoma and colon adenoma), kidney, epidermis, liver, lung (For example, exocrine pancreatic carcinoma), stomach, cervix, thyroid, nose, head and neck, prostate and skin (e.g., squamous cell carcinoma, squamous cell carcinoma, Cell carcinomas), but are not limited thereto. Other examples of cancers that can be treated with the compounds of the present invention include hematopoietic tumors of the lymphatic system such as leukemia, acute lymphoblastic leukemia, mantle cell lymphoma, chronic lymphocytic leukemia, B-cell lymphoma (e.g., diffuse large B cell lymphoma ), T-cell lymphoma, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and buckling lymphoma; Myeloid hematopoietic tumors such as acute and chronic myelogenous leukemia, myelodysplastic syndrome, and premenstrual leukemia. Other cancers include thyroid follicular cancer; Tumors of mesenchymal origin, such as fibrosarcoma or rhabdomyosarcoma; Tumors of the central or peripheral nervous system, such as astrocytomas, neuroblastoma, glioma or schwannomas; Melanoma; Normal species; Malignant carcinoma; Osteosarcoma; Pigmented scleroderma; Retinoblastoma; Each parietal cell tumor; Thyroid follicular cancer; And Kaposi &apos; s sarcoma.

One group of cancers is human breast cancer (e.g., primary breast tumor, nodule-negative breast cancer, invasive ductal adenocarcinoma of the breast, non-endometrial breast cancer); And endometrial cancer. Another subset of cancers in which compounds with CDK4 / 6 inhibitory activity may have particular therapeutic benefit include polymorphic glioblastoma, T cell ALL, sarcoma, familial melanoma and melanoma.

CDK4 / 6 inhibitors are also useful for the treatment of viral infections, such as herpes viruses, poxviruses, Epstein-Barr viruses, Sindbis viruses, adenoviruses, HIV, HPV, HCV and HCMV; Prevention of AIDS outbreak in HIV-infected individuals; Chronic inflammatory diseases such as systemic lupus erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease and autoimmune diabetes; Cardiovascular diseases such as cardiac hypertrophy, restenosis, atherosclerosis; Neurodegenerative disorders such as Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, pigmented retinitis, spinal muscular atrophy and cerebellar degeneration; Glomerulonephritis; Ischemic injury associated with myelodysplastic syndrome, myocardial infarction, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol-related liver disease, blood diseases such as chronic anemia and aplastic anemia; May be useful in the treatment of degenerative diseases of the musculoskeletal system such as osteoporosis and arthritis, aspirin-sensitive sinus rhinitis, cystic fibrosis, multiple sclerosis, kidney disease, ophthalmic diseases such as age related macular degeneration, uveitis and cancer pain.

The methods of treatment of the present invention comprise administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. Individual embodiments of the present invention include any of the above-mentioned disorders or diseases by administering an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof, to a subject in need of treatment of any one of the above mentioned disorders or diseases &Lt; / RTI &gt;

Term "therapeutically effective amount" of a compound of the present invention means a biological or medical response of a subject, for example, a decrease or inhibition of enzyme or protein activity, or an improvement in symptoms, alleviation of a condition, slowing or delaying disease progression, &Lt; / RTI &gt; and the like. (I) CDK4 / 6 mediated, or (ii) CDK4 / 6 activity, or (ii) CDK4 / 6 activity. iii) effective to at least partially ameliorate, inhibit, prevent and / or ameliorate a condition or disorder or disease characterized by the activity (normal or abnormal) of CDK4 / 6; Or (2) effective to reduce or inhibit the activity of CDK4 / 6; Or (3) an amount of a compound of the invention effective to reduce or inhibit the expression of CDK4 / 6. In another non-limiting embodiment, the term "therapeutically effective amount" is effective to at least partially reduce or inhibit the activity of CDK4 / 6 when administered to a cell, tissue, non-cell biological material, or media; Quot; refers to an amount of a compound of the invention that is effective at least partially reducing or inhibiting the expression of CDK4 / 6. The term "therapeutically effective amount" as that term is exemplified in the above embodiments for CDK4 / 6 also applies to any other related protein / peptide / enzyme in the same sense.

The term "subject" as used herein refers to an animal. Typically, the animal is a mammal. The term also refers to, for example, primates (e.g., human, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In another embodiment, the subject is a human.

As used herein, the term "treating", "treating", "treating", or "treating" any disease or disorder refers, in one embodiment, to an improvement in a disease or disorder (ie, Slowing or inhibiting or reducing the onset of symptoms). In another embodiment, "treating "," treating ", or "treating" refers to alleviating or ameliorating one or more physical parameters, including those that may not be recognizable by the patient. In another embodiment, "treating "," treating ", or "treating" means treating a disease or disorder physically (e.g., stabilizing a recognizable symptom), physiologically (e.g., stabilizing a physical parameter) Or both. In another embodiment, "treating "," treating "or" treating "refers to preventing or delaying the onset or development or progression of a disease or disorder.

As used herein, when a subject is beneficially biologically, medically or in quality of life from treatment, the subject is "necessary" for such treatment.

The pharmaceutical composition or combination of the present invention may contain about 1-1000 mg of active ingredient (s), or about 1-500 mg, about 1-250 mg, about 1-150 mg, about 0.5-100 mg, or about 1-50 mg of the active ingredient per unit dose. The therapeutically effective dose of the compound, pharmaceutical composition or combination thereof will vary depending upon the species, weight, age and individual condition of the subject, the disorder or disease to be treated, or the severity thereof. An ordinary physician, clinician, or veterinarian can readily determine the effective amount of each active ingredient required to prevent, treat, or inhibit the progression of a disorder or disease.

The above-cited dosage characteristics can advantageously be demonstrated in in vitro and in vivo studies using mammals, such as mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. The compounds of the present invention may be applied in vitro in the form of solutions, e. G. Aqueous solutions, and may be applied in vivo, rectally, parenterally, advantageously intravenously, e. G. In the form of suspensions or aqueous solutions. The in vitro dose may range from about 10 ^-3 molar to 10 ^-9 molar concentrations. An in vivo therapeutically effective amount may range from about 0.1-500 mg / kg or about 1-100 mg / kg, depending on the route of administration.

One embodiment of the invention includes a method of modulating CDK4 / 6 activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a method of treating a disorder or disease mediated by CDK4 / 6 comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, Of the disorder or disease.

Another embodiment of the present invention is a method for the treatment of a disorder or condition mediated by CDK4 / 6, comprising the administration of a therapeutically effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof, Wherein the disorder or disease is selected from the group consisting of a carcinoma having a gene abnormality that activates CDK4 / 6 kinase activity. These include, but are not limited to, cancers with D-Cyclin potential, such as mantle cell lymphomas and multiple myeloma, cancers with D-cyclin amplification such as breast and squamous cell carcinomas, cancers with CDK4 amplification such as liposarcoma, CDK6 amplification or overexpression But are not limited to, cancers having cancer, such as T-cell lymphoma, and cancers with p16 inactivation, such as melanoma, non-small cell lung cancer and pancreatic cancer.

Another embodiment of the invention is the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the treatment of a disorder or disease mediated by CDK4.

Another embodiment of the present invention is the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the treatment of a disorder or disease mediated by CDK4 in a subject, wherein said disorder or disease is CDK4 / 6 kinase activity And a carcinoma having an activating gene abnormality. These include, but are not limited to, cancers with D-Cyclin potential, such as mantle cell lymphomas and multiple myeloma, cancers with D-cyclin amplification such as breast and squamous cell carcinomas, cancers with CDK4 amplification such as liposarcoma, CDK6 amplification or overexpression But are not limited to, cancers having cancer, such as T-cell lymphoma, and cancers with p16 inactivation, such as melanoma, non-small cell lung cancer, and pancreatic cancer.

Another embodiment of the present invention is a compound according to formula I, or a pharmaceutically acceptable salt thereof, for use as a medicament.

Another embodiment of the invention is the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disorder or disease mediated by CDK4 / 6, wherein the disorder or disease is a CDK4 / 6 kinase activity Lt; RTI ID = 0.0 &gt; a &lt; / RTI &gt; These include, but are not limited to, cancers with D-Cyclin potential, such as mantle cell lymphomas and multiple myeloma, cancers with D-cyclin amplification such as breast and squamous cell carcinomas, cancers with CDK4 amplification such as liposarcoma, CDK6 amplification or overexpression But are not limited to, cancers having cancer, such as T-cell lymphoma, and cancers with p16 inactivation, such as melanoma, non-small cell lung cancer, and pancreatic cancer.

Combination

The compounds of the present invention may be administered concurrently with, or before or after, one or more other therapeutic agents. The compounds of the present invention may be administered individually, by the same or different routes of administration, or may be administered together in the same pharmaceutical composition as other agents.

In one embodiment, the invention provides a product comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents as a combination agent for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is treatment of a disease or condition mediated by CDK4 / 6 inhibition. The product provided as a combination preparation may comprise the compound of the present invention and the other therapeutic agent (s) in the form of, for example, a kit, in a composition comprising the compound of the present invention and the other therapeutic agent &Lt; / RTI &gt;

In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and another therapeutic agent (s). Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable excipient as described above.

In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of Formula I, or a pharmaceutically acceptable salt thereof. In one embodiment, the kit comprises means for individually retaining the composition, such as a container, a divided bottle, or a divided foil packet. An example of such a kit is a blister pack typically used for packaging tablets, capsules, and the like.

The kits of the invention may be used to administer different dosage forms, such as oral and parenteral, for administering the individual compositions at different dosage intervals, or for titrating individual compositions against one another. For convenience, the kits of the present invention typically comprise administration instructions.

In the combination therapy of the present invention, the compounds of the present invention and other therapeutic agents may be manufactured and / or formulated by the same or different manufacturers. In addition, the compounds of the present invention and other therapeutic agents may be administered together (i) before being delivered as a combination product from a physician (e.g., in the case of a kit comprising a compound of the present invention and another therapeutic agent); (ii) by a physician (or under the direction of a physician) immediately prior to administration; (iii) may be used as a combination therapy, for example, in a patient himself during sequential administration of, for example, a compound of the present invention and another therapeutic agent.

Accordingly, the invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the treatment of a disease or condition mediated by the inhibition of CDK4 / 6, wherein the medicament is formulated for administration do. The invention also provides the use of another therapeutic agent for the treatment of a disease or condition mediated by the inhibition of CDK4 / 6, wherein the medicament is administered with a compound of the invention.

The present invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or condition mediated by CDK4 / 6 inhibition, wherein the compound of formula I is administered in combination with another therapeutic agent . The present invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by CDK4 / 6 inhibition, wherein the other therapeutic agent is administered in combination with a compound of formula I, or a pharmaceutically acceptable salt thereof, . The present invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or condition mediated by CDK4 / 6 inhibition, wherein a compound of formula I, or a pharmaceutically acceptable salt thereof, It is administered with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by CDK4 / 6 inhibition, wherein the other therapeutic agent is administered with a compound of formula (I).

The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of a disease or condition mediated by CDK4 / 6, wherein the patient has previously (for example, within 24 hours) I have been treated with other treatments. The present invention also provides the use of another therapeutic agent for the treatment of a disease or condition mediated by CDK4 / 6, wherein the patient has previously been treated with a compound of formula (I) or a pharmaceutically acceptable salt thereof I have been treated with salt.

In one embodiment, the other therapeutic agent is selected from an anti-inflammatory agent, an anti-proliferative agent, a chemotherapeutic agent, an immunosuppressive agent, an anti-cancer agent, a cytotoxic agent, or a kinase inhibitor other than a compound of the present invention or a salt thereof. Additional examples of agents that can be administered in combination with the compounds of the present invention include PTK inhibitors, cyclosporin A, CTLA4-Ig, anti-ICAM-3, anti-IL-2 receptor, anti- CD40, anti-CD4, anti-CD80, anti-CD86 and monoclonal antibody OKT3, an agonist blocking the interaction between CD40 and gp39, a fusion protein consisting of CD40 and gp39, an NF- TNF-alpha inhibitor, anti-TNF antibody or soluble TNF receptor, rapamycin, mTor inhibitor, non-steroidal antiinflammatory drug, steroid, gold compound, antiproliferative agent, FK506, mycophenolate mofetil, cytotoxic drug, TNF- , Leflunimide, cyclooxygenase-2 inhibitor, paclitaxel, cisplatin, carboplatin, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, metopterin, mitomycin C, 743, formiromycin, 5-fluorouracil, But are not limited to, 6-mercaptopurine, gemcitabine, cytosine arabinoside, grape pilotoxin, etoposide, etoposide phosphate, teniposide, melphalan, vinblastine, vincristine, leucocyanine, epothilone, A CDK9 inhibitor, a CDK9 inhibitor, a CDK9 inhibitor, an EGFR inhibitor, a FGFR inhibitor, a PDGFR inhibitor, a Her2 / neu inhibitor, a prodrug, a prodrug, a prodrug, But are not limited to, FLT3 inhibitors, antagonists of androgens, glucocorticoids and prostanone receptors, SMO inhibitors, WNT inhibitors, Bcl inhibitors, IAP inhibitors, Mcl inhibitors, MDM2 inhibitors, p52 inhibitors, proteosome inhibitors (Velcade) , But is not limited thereto.

Certain individual combinations that can provide a particular therapeutic benefit include co-treatment with mTOR inhibitors, such as ravelrolimus, in covert cell lymphoma or pancreatic cancer patients.

The compounds of the present invention may also be used in combination with other agonists, e. G., Additional protein kinase inhibitors, which may or may not be compounds of the invention, for the treatment of protein kinase-related disorders in a subject. The term "combination" refers to a fixed combination in the form of a single dosage unit, or a combination of the compounds of the present invention and the combination partner administered at the same time, or in particular the time at which the combination partner causes a cooperative effect, Means a kit of parts for combination administration that can be administered separately within the interval, or any combination thereof.

The compounds of the present invention may be administered simultaneously or sequentially with anti-inflammatory agents, antiproliferative agents, chemotherapeutic agents, immunosuppressive agents, anti-cancer agents, cytotoxic agents, or kinase inhibitors other than compounds of formula I or pharmaceutically acceptable salts thereof. Additional examples of agents that can be administered in combination with the compounds of the present invention include PTK inhibitors, cyclosporin A, CTLA4-Ig, anti-ICAM-3, anti-IL-2 receptor, anti- CD40, anti-CD4, anti-CD80, anti-CD86 and monoclonal antibody OKT3, an agonist blocking the interaction between CD40 and gp39, a fusion protein consisting of CD40 and gp39, an NF- Inhibitors, anti-TNF antibodies or soluble TNF receptors, rapamycin, reflux, non-steroidal antiinflammatory drugs, steroids, gold compounds, antiproliferants, FK506, mycophenolate mofetil, cytotoxic drugs, TNF- Methionine, methotrexate, methotrexate, mitomycin C, extenacidin 743, phorbol tetracycline, carboflastine, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, Pyrumycin, 5-fluorouracil, 6-mercapto The present invention relates to the use of a compound selected from the group consisting of leucine, gemcitabine, cytosine arabinoside, graphexotoxin, etoposide, etoposide phosphate, teniposide, melphalan, vinblastine, vincristine, lyroscidin, epothilone, Or derivatives thereof, but are not limited thereto.

The compounds of the present invention and any additional agents may be formulated in separate dosage forms. Alternatively, to reduce the number of dosage forms administered to a patient, the compounds of the present invention and any additional agents may be formulated together in any combination. For example, the inhibitor compounds of the present invention can be formulated in a single dosage form, and additional agents can be formulated together in yet another dosage form. Any of the individual dosage forms may be administered at the same time or at different times.

Alternatively, the compositions of the present invention comprise additional agents as described herein. Each component may be present as a separate composition, a combination composition, or a single composition.

General Synthetic Procedures and Intermediates

General N-C Coupling Procedure 1

A compound of structure 1 (1 eq.) And a compound of general structure 2 (1 eq.) Were combined in a suitable reaction vessel in a suitable solvent such as, but not limited to, dioxane. To this resulting solution was added palladium (II) acetate (0.1 eq), ligand such as BINAP, XPhos or xantphos (0.15 eq), and cesium carbonate (1.5 eq). Nitrogen was then gently bubbled through the reaction mixture (approximately 5 to 10 minutes). The resulting reaction mixture was then heated to approximately 100-130 DEG C using an oil bath or microwave for a suitable amount of time, indicating that the reaction was complete, by TLC or HPLC MS analysis. The reaction was removed from the heat source and allowed to cool. The mixture was then worked up by addition of an appropriate solvent, such as dichloromethane or ethyl acetate. The insoluble layer was removed by filtration, and the organic filtrate was extracted with water. The aqueous phase was back-extracted. The organic phases were combined, dried over sodium sulfate or magnesium sulfate, filtered and concentrated to give a residue. The crude residue is purified by silica gel chromatography using a suitable mobile phase to yield the desired intermediate or the compound of formula (I).

Nitro group reduction procedure 1

A suitable reaction vessel was charged with the compound of structure 3. The compound of structure 3 is dissolved using a suitable solvent such as methanol, ethyl acetate, tetrahydrofuran or a mixture of these solvents. To the resulting mixture under a stream of nitrogen was added to the structure 3 a catalyst, such as palladium on carbon or palladium hydroxide (5-20% metal on carbon or a suitable support) of 5-10 mole percent. The resulting mixture was then purged and stirred in a hydrogen gas atmosphere. After all of the starting material had been converted into the product as determined by TLC or LCMS, the reaction vessel was removed from the hydrogen source and purged with nitrogen to remove residual hydrogen gas. The reaction mixture is filtered through a pad of celite under a stream of nitrogen and washed with an additional amount of solvent, such as dichloromethane or methanol. The filtrates were combined and concentrated to a residue. The residue was dried under vacuum to constant weight. The resulting material was used directly in the subsequent reaction or purified by recrystallization or silica gel chromatography and then used in the subsequent reaction.

Procedures for the preparation of amides of formula (I)

The corresponding amine of structure 6 was formed by coupling the carboxylic acid of structure 5 with an amine using the following general procedure.

General amide formation method 1

To a solution of carboxylic acid (1.01 mmol) in DMF (5 mL) was added O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU, 1.5 mmol, 1.5 eq.) and N, N-diisopropylethylamine (0.55 mL, 3.0 eq.) were added and the resulting mixture was stirred at room temperature for about 5 min. To the resultant mixture was added amine (1.18 mmol, 1.1 eq.). While stirring at the resulting mixture for completion as determined by TLC or LCMS appropriate time at room temperature, then diluted with ethyl acetate, 0.5M HCl, and washed successively with water, dried over Na ₂ SO _4, filtered, Lt; / RTI &gt; The desired material was immediately used in the next step without further purification, or was purified by silica gel chromatography using the appropriate mobile phase and used directly in the subsequent reaction.

General amide formation method 2

To a solution of the carboxylic acid (salt form containing 5 equivalents of LiCl) (1 mmol, 1 eq.) In DMF (5 mL) was added O- (benzotriazol- (HBTU, 580 mg, 1.53 mmol, 1.5 eq.) And N, N-diisopropylethylamine (0.55 mL, 3.0 eq.) Were added and the resulting mixture was stirred at room temperature Stir for 5 minutes. To the resultant mixture was added amine (1.18 mmol, 1.1 eq.). The mixture was stirred at room temperature for an appropriate time to the completion of the reaction as determined by TLC or LCMS diluted with ethyl acetate and 0.5M HCl, and washed successively with water, dried over Na ₂ SO _4, filtered, and concentrated . The desired material was immediately used in the next step without further purification, or was purified by silica gel chromatography using the appropriate mobile phase and used directly in the subsequent reaction.

General amide formation method 3

To a solution of the carboxylic acid (1 equivalent, containing 5 equivalents of LiCl) in DMA or DMF was added O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium Tetrafluoroborate (TBTU, 1 eq.) Was added and the resulting solution was stirred for about 10 min. Subsequently, 3 ml of additional dichloromethane was added (about 0.03M final concentration), followed by the addition of amine (1 eq) and DIPEA (4 eq) and TLC and / or LCMS until RT Lt; / RTI &gt; The reaction mixture was diluted with dichloromethane, washed with water and then with brine. The combined aqueous layers were back-extracted with dichloromethane. The combined organic layers were dried over sodium sulfate or magnesium sulfate, filtered, then concentrated and finally purified by silica gel column chromatography using the appropriate mobile phase and used directly in the subsequent reaction.

General amide formation method 4

To a suspension / solution of a mixture of carboxylic acid (containing 5 equivalents of LiCl) (1 equivalent) in DMA / DCM (1: 4, 0.07M) was added O- (benzotriazol- N, N ', N'-tetramethyluronium tetrafluoroborate (TBTU, 1.5 eq., General procedure B1) or O- (benzotriazol- (HBTU, 1.5 eq., General procedure B2) was added and the resulting mixture was stirred at room temperature for 5 minutes. The reaction mixture was treated with a solution of amine (1 eq) in DMA / DCM (1: 4, 0.07M) or HCl salt (1.0 eq) of amine in DMA / DCM (1: 4, 0.07M) and sodium bicarbonate Lt; / RTI &gt; The resulting mixture was treated with N, N-diisopropylethylamine (4.0 eq) and stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed, dried over Na ₂ SO ₄ with water, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography using a suitable mobile phase and used in the subsequent reaction.

General procedure for the removal of protecting groups of intermediates

In the intermediate containing the protecting groups required for the synthesis of the final compound of formula I, was removed by standard procedures such as those described in the literature for these protecting groups [ "Protective Groups in Organic Synthesis, 3 rd Edition, by Green and Wutts].

Deprotection method 1: Removal of BOC using HCl

To a stirred solution of the BOC protected amine (1. mmol) in the compound of formula 1 in dichloromethane (4 mL) or other appropriate solvent was added a solution of 4M HCl in dioxane (2.54 mL, 10.2 mmol, 10 eq). The reaction was stirred at room temperature until all starting material was consumed when measured by LCMS or TLC. The reaction mixture is then filtered and washed with a solvent such as dichloromethane, ethyl acetate or diethyl ether. The residue was collected, dissolved in water, basified using 1 M NaOH and extracted with a dichloromethane or 20% isopropyl alcohol-dichloromethane mixture. The combined organic layers were dried over Na ₂ SO _4, filtered, and concentrated under reduced pressure to a residue. The crude residue was purified by silica gel chromatography using the appropriate mobile phase and used directly in the subsequent reaction.

Deprotection method 2: Removal of BOC using trifluoroacetic acid

To a cold 0 ° C stirred solution of the BOC protected amine (1. mmol) of the compound of formula (1) in dichloromethane (4 mL) or other suitable solvent was added 4 ml of trifluoroacetic anhydride. The reaction was stirred at 0 &lt; 0 &gt; C, allowed to warm to room temperature, and stirred until all starting material was consumed as determined by LCMS or TLC. The reaction mixture was then concentrated in vacuo to a thick residue. The residue was extracted with a mixture of dichloromethane and saturated sodium bicarbonate. The aqueous layer was back-extracted with dichloromethane. For highly polar amines, a 20% isopropyl alcohol-dichloromethane mixture was used as the organic extraction solvent. Combine the organic fractions were dried over Na ₂ SO _4, filtered and concentrated under reduced pressure to a residue. The combined organic layers were dried over sodium sulphate or magnesium sulphate, filtered and concentrated to a residue under reduced pressure. The crude residue was purified by silica gel chromatography using the appropriate mobile phase and used directly in the subsequent reaction.

Deprotection method 3: BOC removal using trifluoroacetic acid

A solution of the BOC protected amine of compound of formula 1 in CH ₂ Cl ₂ (0.1 M) was treated with an equivalent volume of trifluoroacetic acid at room temperature and stirred at room temperature for 1.0 hour. The reaction mixture was concentrated in vacuo, MeOH was treated with a little bit of a 7 N NH ₃ until the mixture became neutral. The resulting mixture was concentrated to a thick residue. The resulting residue was then purified by preparative HPLC or silica gel chromatography using 7 N NH ₃ in MeOH / CH ₂ Cl ₂ and used directly in the subsequent reaction.

General reductive amination procedure

A solution of a compound of formula I containing 1 or 2 equivalents of a primary or secondary amine with an excess of (3-8 equivalents) aldehyde (e.g., formaldehyde, 37% solution in water) or a ketone (e.g. acetone) ) Were combined in a suitable solvent such as tetrahydrofuran and allowed to stir at RT for 1 h with magnesium sulfate (1 eq.). Sodium triacetoxyborohydride (2 eq.) Was then added in one portion and the reaction was allowed to stir until all starting material was consumed as determined by TLC or LCMS. The reaction was then quenched, dissolved in ethyl acetate and saturated Na ₂ CO ₃ Neutralized with solution and washed with brine. The aqueous layer was back-extracted with ethyl acetate. The organic layers were combined, dried over Na ₂ SO _4. For very polar amines, a 20% isopropanol-chloroform solution was used as the extraction solvent. The volatiles were removed and the resulting residue was purified by silica gel chromatography using the appropriate mobile phase to give the desired final product.

2-chloro -7 R ¹ -N, N- dimethyl -7H- pyrrolo [2,3-d] pyrimidine-6-carboxamide The procedure for the preparation of a carboxamide intermediate.

2-Chloro-7R2-N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-

Intermediate 1:

Preparation of 2-chloro-7-cycloheptyl-N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

Step 1

To a solution of 5-bromo-2,4-dichloropyrimidine (13.41 g, 58.8 mmol) in EtOAc (100 mL) was added DIPEA (13 mL, 1.3 eq) followed by cycloheptanamine (8.6 mL, 1.1 eq) And the resulting mixture was stirred at room temperature for 5 days. The reaction mixture was diluted with EtOAc (350 mL), washed with water (100 mL), brine (2 x 100 mL), dried over Na ₂ SO ₄ and was filtered and concentrated. The crude product (18.1 g) was used in the subsequent reaction without purification.

Step 2

Preparation of 3- (2-chloro-4- (cycloheptylamino) pyrimidin-5-yl) prop-2-yn-

To a yellow solution of 5-bromo-2-chloro-N-cycloheptylpyrimidin-4-amine (18.1 g, 55.5 mmol) in THF (200 mL) was added propargyl alcohol (4.5 mL, 1.4 eq.) And THF 1 M, 130 mL, 2.3 eq.) Was added and the resulting brown mixture was treated with a stream of nitrogen (bubbling in solution) for 15 min. The mixture was then treated with bis (triphenylphosphine) palladium (II) chloride (2.09 g, 0.054 eq) and heated to reflux for 5 hours. After cooling, the reaction mixture was filtered through a pad of celite (rinsing with about 350 mL of EtOAc). The filtrate was concentrated to remove THF, diluted with additional EtOAc (total volume 250 mL), washed with saturated NaHCO ₃ (2 x 150 mL) and water (150 mL), dried over Na ₂ SO ₄ , Filtered and concentrated. The residue was triturated in acetone and CH ₂ Cl ₂ to give 56% of 3- (2-chloro-4- (cycloheptylamino) pyrimidin-5-yl) &Lt; / RTI &gt;

Step 3

(2-chloro-7-cycloheptyl-7H-pyrrolo [2,3-d] pyrimidin-6-yl) methanol.

To a suspension of 3- (2-chloro-4- (cycloheptylamino) pyrimidin-5-yl) prop-2-yn-1-ol (8.64 g, 30.9 mmol) in THF (200 mL) (1 M, 66 mL, 2.1 eq) was added and the resulting mixture was heated at 63 &lt; 0 &gt; C for 5 h. The reaction mixture was concentrated to remove the THF, diluted with EtOAc (350 mL), washed with water (140 mL) and brine (140 mL), dried over Na ₂ SO _4, filtered, and concentrated. The residue was triturated with iPrOH, CH ₂ Cl ₂ and MeCN followed by column chromatography (EtOAc / heptane 20 → 100%) of the mother liquor to give (2-chloro-7-cycloheptyl-7H- 2,3-d] pyrimidin-6-yl) methanol (6.24 g) in 72% yield.

Step 4

Preparation of 2-chloro-7-cycloheptyl-N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

To a solution of (2-chloro-7-cycloheptyl-7H-pyrrolo [2,3-d] pyrimidin-6- yl) methanol (6.24 g, 22.3 mmol) in DMF (100 mL) A solution (2 M, 46 mL, 4.1 eq) and sodium cyanide (1.04 g, 0.95 eq) were added and the resulting mixture was stirred at room temperature for 4 min. The reaction mixture was treated in four portions over 1 hour with manganese dioxide (100.4 g, 45 eq) and stirred for an additional hour. The reaction mixture was filtered through a pad of celite (rinsed with 600 mL of EtOAc). The filtrate was washed with water (200 mL). The aqueous phase was extracted with EtOAc (2 x 150 mL). The combined organic portions washed with a 4% aqueous solution (2 x 250 mL) of NaCl, dried over Na ₂ SO _4, filtered, and concentrated under vacuum. The residue was triturated in MeCN followed by column chromatography (EtOAc / heptane 30 → 100%) of the mother liquor to give 2-chloro-7-cycloheptyl-N, d] pyrimidine-6-carboxamide (6.07 g) was obtained in 85% yield.

Intermediate 2:

Pyrrolo [2,3-d] pyrimidine-6-carboxamide was prepared in a manner analogous to Intermediate 1, but substituting N, N-dimethyl-

Step 1

(23.2 g, 78% yield): &lt; RTI ID = 0.0 &gt;

Step 2

Yield: 9.1 g (43% yield): 3- (2-Chloro-4-cyclohexylaminopyrimidin-

Step 3

Pyrrolo [2,3-d] pyrimidin-6-yl) -methanol (7.3 g, 81% yield):

Step 4

Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (0.85 g, 64% yield):

Intermediate 3:

2-Chloro-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide was prepared in a similar manner according to the procedure for the preparation of Intermediate 1 , Which is a known document compound (see WO 2010/020675).

Intermediate 4:

Pyrrolor2,3-dlpyrimidin-6 (2-chloro-N, N-dimethyl-7- (tetrahydro- -Carboxamide &lt; / RTI &gt; were prepared in a similar manner.

Step 1

(Tetrahydro-2H-pyran-3-yl) pyrimidin-4-amine (6.47 g) was prepared in 83% yield.

Step 2

Ylamino) pyrimidin-5-yl) prop-2-yn-1-ol (3.21 g) was prepared in 54% yield .

Step 3

Pyrrolo [2,3-d] pyrimidin-6-yl) methanol (2.39 g) was prepared in 75% yield .

Step 4

Pyrrolo [2,3-d] pyrimidine-6-carboxamide (1.74 g) was obtained as a pale yellow amorphous solid in 58 % Yield.

Intermediate 5

2,3-d] pyrimidin-2-ylmethyl) -piperazin-1-yl] -pyrrolidine The title compound was prepared according to the procedure for the preparation of Intermediate 1 from 2-chloro-7- (4- Pyrimidine-6-carboxamide was prepared in a manner analogous to Intermediate 1.

Step 1:

2- (4- (5-bromo-2-chloropyrimidin-4-ylamino) phenyl) -2- methylpropanenitrile

(1.96 g, 6 mmol), 2- (4-aminophenyl) -2-methylpropanenitrile (0.96 g, 6 mmol) and diisopropylethylamine , 9 mmol) were combined in 30 ml acetonitrile and stirred at room temperature for 16 hours. At 16 hours, LC / MS indicated that the reaction was complete. The organic portion was washed sequentially with 1 M citric acid solution, water, then brine. The organic portion was dried over sodium sulfate, then triturated and evaporated to give the crude material which was used directly in the next step. (1.45 g, 69%).

Step 2:

2- (4- (2-Chloro-5- (3-hydroxyprop-1-ynyl) pyrimidin-4-ylamino) phenyl) -2-methylpropanenitrile.

2- (4- (5-bromo-2-chloropyrimidin-4-ylamino) phenyl) -2- methylpropanenitrile (1.4 g, 3.98 mmol), bis (triphenylphosphine) Palladium (II) chloride (0.14 g, 0.2 mmol), tetrabutylammonium fluoride (2.6 g, 9.95 mmol) and propargyl alcohol (0.357 mL, 5.97 mmol) were combined in 12 mL THF and heated in a 70 0 C oil bath Respectively. After 2 h, the reaction was complete by LC / MS. The volatiles were removed and the residue was dissolved in EtOAc. The organic layer was filtered to remove insoluble soot. The organic layer was washed with water, brine, and then dried over sodium sulfate. The volatiles were removed and the residue was purified by NPLC (10-75% EtOAc in heptane, Analogix). (869 mg, 67%).

Step 3:

2- (4- (2-Chloro-6- (hydroxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) phenyl) -2-methylpropanenitrile.

2- (4- (2-chloro-5- (3-hydroxyprop-1-ynyl) pyrimidin-4- ylamino) phenyl) -2- methylpropanenitrile was further dried Was reacted with a solution of 1M tetrabutylammonium fluoride in THF (5.85 mL, 5.85 mmol) diluted to 10 mL with THF. Analytical LC indicated that the reaction was complete (minimal migration of residence time). The volatiles were removed and the residue was dissolved in ethyl acetate. The organic portion was washed with water, brine, and then dried over sodium sulfate. The volatiles were removed and the residue was purified by NPLC (10-75% ethyl acetate in heptane, Analogics) to give the desired product (589 mg, 68%).

Step 4:

Yl) phenyl] -N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide.

Phenyl) -2-methylpropanenitrile (589 mg, 1.8 mmol) was added to a solution of 2- (4- (2-chloro-6- (hydroxymethyl) -7H- pyrrolo [2,3- d] pyrimidin- ), Manganese dioxide (7.8 g, 90 mmol) and a 2 M dimethylamine solution in THF (4.51 ml, 9 mmol) were combined in 6 mL of dry DMF. The reaction was stirred for 3 hours, and as a result LC / MS showed the reaction to be complete. The reaction was poured into brine and extracted with EtOAc. The combined organic portions were washed with water, followed by brine, and then dried over sodium sulfate. The volatiles were removed and the residue was purified by NPLC (10-100% ethyl acetate in heptane, Analogics) to give the pure desired compound. (345 mg, 52%).

Intermediate 6

Pyrrolo [2,3-d] pyrimidin-2-ylamino) nicotinic acid LiCl salt &lt; EMI ID =

Step 1

Preparation of methyl 6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3-d] pyrimidin-2-ylamino) nicotinate.

To a solution of 2-chloro-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide ( (2.86 g, 1.10 eq.), Pd (OAc) ₂ (0.096 g, 0.025 eq.) And BINAP (0.532 g, 0.050 eq.) Were added to a suspension of . N ₂ was degassed by bubbling through the resulting mixture for 20 minutes and treated with Cs ₂ CO ₃ (8.35 g, 1.5 eq). The reaction mixture was heated at 100 &lt; 0 &gt; C for 2.2 hours. The reaction mixture was cooled to room temperature, treated with 100 mL of heptane, and sonicated. The red precipitate was collected by filtration and suspended in 200 mL of water. After sonication, the solid was collected by filtration, rinsed with water (3 x 50 mL) and dried. The solid was triturated in THF to yield a tan solid solid of methyl 6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3- d] pyrimidin- 2-ylamino) nicotinate 6.6 g, 94% yield). The filtrate was concentrated in vacuo and purified by column chromatography (ethyl acetate / heptane) to give additional product (0.4 g, 6% yield).

Step 2

Preparation of 6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3-d] pyrimidin-2-ylamino) nicotinic acid LiCl salt.

To a solution of methyl 6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3-d] pyrimidin-2- ylamino) nicotinate (0.29 g, 5.0 eq.) and water (12 mL) and the resulting mixture was stirred at 60 &lt; 0 &gt; C for 1 hour. The suspension slowly became clear. After cooling to room temperature, the reaction mixture was treated with 1 N HCl (12.24 mL, 5 eq) and concentrated in vacuo. A light yellow solid (1.40 g) of a mixture of 6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H- pyrrolo [2,3- d] pyrimidin- 2-ylamino) nicotinic acid and LiCl g, 95% yield) was used in the subsequent reaction without further purification.

Intermediate 7

Preparation of 6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3-d] pyrimidin-2-ylamino) nicotinic acid.

To a solution of methyl 6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3-d] pyrimidin-2- ylamino) nicotinate (2.0 g, 4.9 mmol) was added 1M LiOH (aq) (6 mL, 1.2 eq) and the slurry was stirred at 45 &lt; 0 &gt; C for 12 h (the slurry became clear). After cooling to room temperature, the THF was evaporated and the reaction mixture was treated with 1 N HCl until pH = 1-2. The resulting precipitate was filtered, the filtrate was extracted with 20% isopropanol / CH ₂ Cl ₂ (3 x 100 mL) and the combined organic layers were dried, filtered and concentrated to give a tan solid. The tan solid was triturated in acetone to afford 6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3-d] pyrimidin- 2- ylamino) nicotinic acid as a tan solid g, 73% yield) as the desired product which was used without further purification.

Intermediate 8

2,3-d] pyrimidin-2-ylmethyl) -piperazin-1-yl] -pyrrolidine The title compound was prepared according to the procedure for the preparation of Intermediate 1 from 2-chloro-7- (4- Pyrimidine-6-carboxamide was prepared in a manner analogous to Intermediate 1.

6- (7-Cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3-d] pyrimidin-2-ylamino) -nicotinic acid.

Step 1

Carboxylic acid dimethylamide (517 mg, 1.2 mmol, 1.0 eq.), 6-amino-nicotinic acid methyl ester (221 &lt; mixture of N ₂ was bubbled for 3 minutes through a pipette in mg, 1.5 mmol, 1.2 _{equiv), Cs 2 CO 3 (591} mg, 1.8 mmol, 1.5 eq) and BINAP (38 mg, 0.06 mmol, 0.05 equiv) . Pd (OAc) ₂ (14 mg, 0.06 mmol, 0.05 eq) And the flask was sealed and stirred in an oil bath heated to 130 DEG C for 3 hours. The mixture was filtered through a pad of celite and washed with EtOAc. The organic layer with water then washed with brine, The organic layers were combined, dried over Na ₂ SO _4. The solvent was evaporated and the brown solid was triturated with acetonitrile, filtered, washed with ACN and dried under high vacuum to give the title compound as a light pink solid (236 mg, 0.53 mmol, 44% yield).

Step 2

Preparation of 6- (7-cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3-d] pyrimidin-2- ylamino) -nicotinic acid

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -nicotinic acid methyl ester (146 mg, 0.33 mmol) in THF (1.5 mL) , 1.0 eq.) In THF (10 mL) was added LiOH (94.7 mg, 4.0 mmol, 12 equiv.) In 1.5 mL water. The mixture was stirred at room temperature for 48 hours. The reaction mixture was cooled in an ice bath to 0 &lt; 0 &gt; C and acidified with 1 N HCl until the pH was about 1-2. The solid precipitate was filtered off and washed to give the title compound as a light pink solid (52 mg, 0.124 mmol, 37%) which was used as is (Alternatively, it can be extracted with 20% isopropanol in dichloromethane).

Intermediate 9

Pyrrolo [2,3-d] pyrimidin-2-ylamino) nicotinic acid and 5 eq. (1 mmol) Of LiCl was prepared in a similar manner to Intermediate 6.

Example

Example 1

Synthesis of 7-cyclopentyl-2- (5 - ((1R, 5S) -9-hydroxy-3,7-diazabicyclo [3.3.1] , N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide

Step 1.

Preparation of methyl 6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3-d] pyrimidin-2-ylamino) nicotinate.

7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide (5.0 g, 17 mmol) Aminonicotinate (2.86 g, 1.10 eq.) Was combined with methyl 6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3- d] pyrimidin- -Ylamino) nicotinate (6.6 g) in 94% yield.

Step 2.

Preparation of 6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3-d] pyrimidin-2-ylamino) nicotinic acid and 5 equivalents of LiCl.

To a solution of methyl 6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3-d] pyrimidin-2- ylamino) nicotinate (0.29 g, 5.0 eq.) and water (12 mL) and the resulting mixture was stirred at 60 &lt; 0 &gt; C for 1 hour. After cooling to room temperature, the reaction mixture was treated with 1 N HCl (12.24 mL, 5 eq.) And concentrated in vacuo to give 6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [ , 3-d] pyrimidin-2-ylamino) nicotinic acid was obtained in 95% yield as a LiCl (5 eq.) Co-salt as a pale yellow solid (1.40 g) and used without further purification in the subsequent reaction.

Step 3.

According to general amide formation method 1, 6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3-d] pyrimidin- ) Nicotinic acid was combined with (lR, 5S) -tert-butyl 9-hydroxy-3,7-diazabicyclo [3.3.1] Pyrrolo [2,3-d] pyrimidin-2-ylamino) nicotinoyl) -9-hydroxy-3,7- Diazabicyclo [3.3.1] nonane-3-carboxylate (158 mg) was obtained in 77% yield.

Step 4.

Synthesis of 7-cyclopentyl-2- (5 - ((1R, 5S) -9-hydroxy-3,7-diazabicyclo [3.3.1] , N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

Deprotection According to Method 2, (lR, 5S) -tert-butyl 7- (6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3- d] pyrimidin- Cyclopentyl-2- (5 - ((1R, 5S (3H) -quinolinone) nicotinoyl) -9-hydroxy-3,7-diazabicyclo [3.3.1] non- Pyridin-2-yl) -9-hydroxy-3,7-diazabicyclo [3.3.1] ] Pyrimidine-6-carboxamide (47 mg) in 93% yield.

Example 2

3-carbonyl) pyridin-2-ylamino) - [Lambda] / - cycloheptyl-2- (5 - ((1R, 5S) , N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide

Step 1.

Preparation of 6- (7-cycloheptyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3-d] pyrimidin-2-ylamino) nicotinic acid-5LiCl.

Pyrrolor2.3-d] pyrimidin-2-ylamino) -nicotinic acid (prepared as described in step 1) in a manner analogous to that of Example 1, Methyl ester (1.34 g) in 52% yield.

Step 2.

Preparation of 6- (7-cycloheptyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3-d] pyrimidin-2- ylamino) nicotinic acid and 5 equivalents of LiCl

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidin- Nicotinic acid - 5 equivalents of LiCl (1.87 g) was obtained in quantitative yield.

Step 3.

3-carbonyl) pyridin-2-ylamino) - [Lambda] / - cycloheptyl-2- (5 - ((1R, 5S) , N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide.

According to general amide formation method 1, 6- (7-cycloheptyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3-d] pyrimidin- ) Nicotinic acid was combined with (lR, 5S) -tert-butyl 9-hydroxy-3,7-diazabicyclo [3.3.1] Pyrrolo [2,3-d] pyrimidin-2-ylamino) nicotinoyl) -9-hydroxy-3,7-dihydro- Diazabicyclo [3.3.1] nonane-3-carboxylate (170 mg) was obtained in 83% yield.

Step 4.

3-carbonyl) pyridin-2-ylamino) - [Lambda] / - cycloheptyl-2- (5 - ((1R, 5S) , N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

Deprotection According to Method 2, the title compound was obtained from (lR, 5S) -tert-butyl 7- (6- (7-cycloheptyl-6- (dimethylcarbamoyl) -7H- pyrrolo [2,3- d] pyrimidin- 2-ylamino) nicotinoyl) -9-hydroxy-3,7-diazabicyclo [3.3.1] nonane- 3-carboxylate was prepared from 7-cycloheptyl- 2- (5- ( Pyridin-2-yl) -9-hydroxy-3,7-diazabicyclo [3.3.1] ] Pyrimidine-6-carboxamide (43 mg) in 96% yield.

Example 3

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- d] pyrimidine-6-carboxylic acid dimethylamide

Step 1.

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -2,5-dimethyl- Diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester

According to general amide formation method 1, a mixture of 6- (7-cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin-2- ylamino) -nicotinic acid (52.5 mg, , 1.0 eq.) Was combined with 2,5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (32.0 mg, 0.162 mmol, 1.5 eq.) To give 5- [6- Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -2,5-diaza-bicyclo [2.2. 1] heptane-2-carboxylic acid tert-butyl ester (59 mg, 0.09 mmol, 76% yield).

Step 2.

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- d] pyrimidine-6-carboxylic acid dimethylamide.

Deprotection According to Method 1, 5- [6- (7-cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2- ylamino) -pyridine- -2,5-diaza- bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (50 mg, 0.083 mmol, 1.0 eq.) Was added to a solution of 7-cycloheptyl- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethyl ester, Amide to yield 57% as a white solid (24 mg, 0.05 mmol).

Example 4

2-ylamino) -7-cycloheptyl-N, N-dimethyl-7H-pyrrolo [2, 5-dibabicyclo [3.2.1] octane- , 3-d] pyrimidine-6-carboxamide

Step 1.

pyrrolo [2,3-d] pyrimidin-2-ylamino) nicotinoyl) -3,8 (dimethylcarbamoyl) - diazabicyclo [3.2.1] octane-8-carboxylate

Amide The title compound was prepared according to Method 1 from 6- (7-cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3-d] pyrimidin- 2- ylamino) -nicotinic acid (75 mg, 1.0 g) was combined with tert-butyl 3,8-diazabicyclo [3.2.1] octane-8-carboxylate (37.7 mg, 0.18 mmol, 1.0 eq.) To give tert- butyl 3- (Dimethylcarbamoyl) -7H-pyrrolo [2,3-d] pyrimidin-2-ylamino) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8 -Carboxylate as a white solid (80 mg, 0.130 mmol, 73% yield).

Step 2.

2-ylamino) -7-cycloheptyl-N, N-dimethyl-7H-pyrrolo [2, 5-dibabicyclo [3.2.1] octane- , 3-d] pyrimidine-6-carboxamide

Deprotection According to Method 1, tert-butyl 3- (6- (7-cycloheptyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3- d] pyrimidin- Diazabicyclo [3.2.1] octane-8-carboxylate with 2- (5- (3,8-diazabicyclo [3.2.1] octane-3- carbonyl) pyridine Pyrrolo [2,3-d] pyrimidine-6-carboxamide as a white solid (60 mg, 0.116 mmol) Yield.

Example 5

Pyridin-2-ylamino) -7-cycloheptyl-N, N-dimethyl-7H-pyrrolo [2,3 / RTI &gt; d] pyrimidine-6-carboxamide

Step 1.

pyrrolo [2,3-d] pyrimidin-2-ylamino) nicotinoyl) -2,7-dihydro-7H-pyrrolo [ -Diazaspiro [3.5] nonane-2-carboxylate

According to general amide formation method 1, a mixture of 6- (7-cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2- ylamino) -nicotinic acid (80 mg, 0.19 mmol , 1.0 eq.) Was combined with tert-butyl 2,7-diazaspiro [3.5] nonane-2-carboxylate (47.1 mg, 0.208 mmol, 1.1 eq.) To give tert- butyl 7- Pyrrolo [2,3-d] pyrimidin-2-ylamino) nicotinoyl) -2,7-diazaspiro [3.5] The rate was obtained as a white solid (22 mg, 0.035 mmol) in 18.4% yield.

Step 2.

Pyridin-2-ylamino) -7-cycloheptyl-N, N-dimethyl-7H-pyrrolo [2,3 -d] pyrimidine-6-carboxamide &lt; / RTI &gt;

According to the deprotection method 1, tert-butyl 7- (6- (7-cycloheptyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3- d] pyrimidin- (3,5-diazaspiro [3.5] nonane-7-carbonyl) pyridin-2-yl Amino-7-cycloheptyl-N, N-dimethyl-7H-pyrrolo [2,3- d] pyrimidine-6- carboxamide as an off- white solid (25 mg, 0.05 mmol) .

Example 6

2-ylamino) -N, N-dimethyl-thiazol-2-yl) 7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

Step 1.

Preparation of 3-benzyl-8-methyl-3-azabicyclo [3.2.1] octan-8-ol

3-benzyl-3-azabicyclo [3.2.1] octane-8-one (200 mg, 0.93 mmol) with Et ₂ O ₍₂ ml) and dissolved in, Et ₂ O of MeMgBr (1M Et ₂ O solution of 3 ml ) In &lt; / RTI &gt; The resulting reaction mixture was stirred overnight at room temperature. The mixture was diluted with Et ₂ O and washed with saturated aqueous NH ₄ Cl solution and 1 N NaOH. The aqueous layer was extracted with Et ₂ O. The combined organic layers were dried over Na ₂ SO _4, filtered, and concentrated to yield the benzyl-8-methyl-3-azabicyclo [3.2.1] octane-8-ol (110 mg, 51% yield).

Step 2.

Preparation of 8-methyl-3-azabicyclo [3.2.1] octan-8-ol

A sample of 3-benzyl-8-methyl-3-azabicyclo [3.2.1] octan-8-ol (110 mg, 0.48 mmol) was dissolved in MeOH (20 ml) and the atmosphere was replaced with N ₂ Respectively. 10% Pd / C (catalytic amount) was added and the atmosphere was replaced with H ₂ (3X). The resulting reaction mixture was stirred overnight at RT under balloon pressure. When the TLC no longer showed a UV active spot, Pd / C was filtered off (always kept wet with MeOH) and the filtrate was concentrated to give 8-methyl-3-azabicyclo [3.2.1] Ol (70 mg, 99% yield). NMR no longer showed benzyl. Respectively.

Step 3.

2-ylamino) -N, N-dimethyl-thiazol-2-yl) 7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

Pyrrolo [2,3-d] pyrimidin-2-ylamino) nicotinic acid was reacted with 8-methyl-pyrrolidine according to General Amide Formation Method 3 to give 6- (7- 8-hydroxy-8-methyl-3-azabicyclo [3.2.1] octane-8-ol was obtained by combining 7-cycloheptyl-2- (5- (8- Pyrrolo [2,3-d] pyrimidine-6-carboxamide (68 mg) was obtained in 26% yield.

Example 7

2.2.1] heptane-2-carbonyl) pyridin-2-ylamino) -N, N-dihydro- Dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

Pyrrolo [2,3-d] pyrimidin-2-ylamino) nicotinic acid was reacted with (lR, 4R (2R) , 7R) -7-hydroxy-2-azabicyclo [2.2.1] heptan-7- Pyrrolo [2,3-d] pyrimidine-6-carboxamide (50 mg) was dissolved in 77% &Lt; / RTI &gt;

Example 8

Synthesis of 2- (5- (8-acetyl-3,8-diazabicyclo [3.2.1] octane-3-carbonyl) pyridin- Pyrrolo [2,3-d] pyrimidine-6-carboxamide

Pyrrolor2.3-d] pyrimidin-2-ylamino) nicotinic acid was reacted with 1- (3-tert-butoxycarbonylamino) (8-acetyl-3,8-diazabicyclo [3.2.1] octane-3-carbonyl) pyridine Pyrrolo [2,3-d] pyrimidine-6-carboxamide (63 mg) was obtained in 88% yield.

Example 9

2-ylamino] -7H-pyrrolo [2,3-c] pyridin-2- d] pyrimidine-6-carboxylic acid dimethylamide

Step 1.

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -3,6-dimethyl- Diaza-bicyclo [3.2.1] octane-6-carboxylic acid tert-butyl ester

According to general amide formation method 1, 6 - (7 - cyclopentyl - 6 - dimethylcarbamoyl - 7H - pyrrolo [2,3 - d] pyrimidin - 2 - ylamino) - nicotinic acid (5 eq. (571 mg, 0.942 mmol) was combined with tert-butyl 3,6-diazabicyclo [3.2.1] octane-6-carboxylate (200 mg, 0.942 mmol) 7H-pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -3,6-diaza- bicyclo [ 3.2.1] octane-6-carboxylic acid tert-butyl ester in 44% yield in 80% yield.

Step 2.

2-ylamino] -7H-pyrrolo [2,3-c] pyridin-2- d] pyrimidine-6-carboxylic acid dimethylamide

According to the deprotection method 1, 3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2- ylamino) -3,6-diaza-bicyclo [3.2.1] octane-6-carboxylic acid tert-butyl ester was reacted with 7-cyclopentyl-2- [5- (3,6- diaza- bicyclo [ 3.2.1] octane-3-carbonyl) -pyridin-2-ylamino] -7H-pyrrolo [2,3- d] pyrimidine-6- carboxylic acid dimethylamide in dichloromethane ) In 72% yield.

Step 3.

Cyclopentyl-2- [5- (3,6-diaza-bicyclo [3.2.1] octane-3-carbonyl) -pyridin-2- ylamino] -7H- pyrrolo [2 H, 4.6 x 100 mm, SFC, 4 g / min, 40 C, 30 &lt; RTI ID = 0.0 &gt; Cyclopentyl-2- [5 - ((1S, 5S) -3,6-diaza-bicyclo [3.2.1] octane-3-ene- Yl) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (isomer 1) and 7-cyclopentyl-2- [5- Pyrrolo [2,3-d] pyrimidin-2-ylamino) -thiazole-5-carboxylic acid ethyl ester was prepared from (lR, 5R) -3,6-diaza-bicyclo [3.2.1] octane- 6-carboxylic acid dimethylamide (isomer 2).

Example 10

3-carbonyl) -pyridin-2-ylamino] -thiophene-2-carboxylic acid tert- -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Example 11

3-carbonyl) -pyridin-2-ylamino] -thiophene-2-carboxylic acid tert- -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Example 12

Cyclopentyl-2- {5- [6- (2,2,2-trifluoro-ethyl) -3,6-diaza- bicyclo [3.2.1] octane- 3- carbonyl] -pyridine Ylamino} -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Cyclopentyl-2- {5- [6- (2,2,2-trifluoro-ethyl) -3,6-diaza- bicyclo [3.2.1] octane- 3- carbonyl] -pyridine Ylamino} -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

In a 100 ml round-bottomed flask, 7-cyclopentyl-2- [5- (3,6-diaza-bicyclo [3.2.1] octane-3- carbonyl) -pyridin- 6-carboxylic acid dimethylamide (165 mg, 0.294 mmol) and DIPEA (0.128 ml, 0.735 mmol) were combined and diluted in dioxane (6.00 ml) A heterogeneous solution was obtained. Potassium carbonate (406 mg, 2.94 mmol) and trifluoroethyl triflate (0.106 ml, 0.735 mmol) were then added to the mixture. The reaction was heated to 50 &lt; 0 &gt; C for 18 hours. LCMS showed 100% conversion. The mixture was diluted in DCM, washed with saturated aqueous solution of NaHCO ₃ and was then washed brine. Then, the organic layer was separated, dried over MgSO _4, and evaporated to give a yellowish solid. The solid was triturated with EtOAc to give 7-cyclopentyl-2- {5- [6- (2,2,2-trifluoro-ethyl) -3,6- diaza- bicyclo [3.2.1] 3-carbonyl] -pyridin-2-ylamino} -7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide in 58% yield.

Example 13

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- 2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- 2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Cyclopentyl-2- [5- (3,6-diaza-bicyclo [3.2.1] octane-3-carbonyl) -thiophene in a 50 mL round bottom flask in MeOH (4.00 ml) / DCM Pyrimidin-6-carboxylic acid dimethylamide (183 mg, 0.326 mmol in water) and formaldehyde (37% solution in water) (0.135 ml, 4.89 mmol) were combined to give a yellow light solution. After stirring at room temperature for 1.5 h, sodium triacetoxyborohydride (90 mg, 0.424 mmol) was added and the reaction was stirred for an additional 12 h. LCMS showed complete conversion. The mixture was then washed with diluted dichloro methane, followed by a saturated aqueous solution of NaHCO ₃ brine. Then, and The combined organic phases were dried over MgSO _4, and evaporated to give a light yellow solid. Ethyl acetate followed by trituration with dichloromethane followed by filtration gave 7-cyclopentyl-2- [5- (6-methyl-3,6-diaza- bicyclo [3.2.1] Pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide in 18% yield.

Example 14

3-aza-bicyclo [3.1.0] hexane-3-carbonyl) -pyridin-2- ylamino] -7-cyclopentyl-7H- pyrrolo [2,3 d] pyrimidine-6-carboxylic acid dimethylamide

Step 1.

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -3-aza- -Bicyclo [3.1.0] hex-1-yl} -carbamic acid tert-butyl ester

Pyrrolor2.3-dPyrimidin-2-ylamino) -nicotinic acid (550 mg, 0.907 mmol) was prepared in accordance with the general method for amide formation method 1 from 6- (7-cyclopentyl-6-dimethylcarbamoyl- Butyl ester (180 mg, 0.907 mmol) was combined with {3- [6- (7-cyclopentyl-6- 3-carbonyl] -3-aza-bicyclo [3.1.0] hex-1-yl} pyrimidin- -Carbamic acid tert-butyl ester (260 mg) in 50% yield.

Step 2.

3-aza-bicyclo [3.1.0] hexane-3-carbonyl) -pyridin-2- ylamino] -7-cyclopentyl-7H- pyrrolo [2,3 -d] pyrimidine-6-carboxylic acid dimethylamide di-hydrochloride.

Deprotection According to Method 1, {3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2- ylamino) -pyridin- Butyl ester (250 mg, 0.435 mmol) was reacted with 2- [5- (1-amino-3-aza-bicyclo [ Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide di-tert-butyl ester - &lt; / RTI &gt; hydrochloride (210 mg).

Step 3.

3-aza-bicyclo [3.1.0] hexane-3-carbonyl) -pyridin-2- ylamino] -7-cyclopentyl-7H-pyrrolo [ 2, 3-d] pyrimidine-6-carboxylic acid dimethylamide was prepared under the following conditions: As-H, 4.6 x 100 mm, SFC, 4 g / by carried out using a 45% MeOH 0.2% DEA (of CO ₂₎ each enantiomer 2- [5 - ((S) -1- amino-3-aza-bicyclo [3.1.0] hexane-3-carboxylic 2-ylamino] -7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide and 2- [5 - ((R) Cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-6-ylamino] Carboxylic &lt; / RTI &gt; acid dimethylamide.

Example 15

3-aza-bicyclo [3.1.0] hexane-3-carbonyl) -pyridin-2- ylamino] -7-cyclopentyl- 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Example 16

3-aza-bicyclo [3.1.0] hexane-3-carbonyl) -pyridin-2- ylamino] -7-cyclopentyl- 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Example 17

3-aza-bicyclo [3.1.0] hexane-3-carbonyl) -pyridin-2- ylamino] -7H- pyrrolo [2, 3-d] pyrimidine-6-carboxylic acid dimethylamide

3-aza-bicyclo [3.1.0] hexane-3-carbonyl) -pyridin-2- ylamino] -7H- pyrrolo [2, 3-d] pyrimidine-6-carboxylic acid dimethylamide

In a 50 mL round bottom flask, a solution of 2- [5- (1-amino-3-aza-bicyclo [3.1.0] hexane-3- Carboxylic acid dimethylamide (k) (200 mg, 0.421 mmol) and the compound of formula &lt; RTI ID = 0.0 & Aldehyde (37% in water) (0.967 ml, 10.54 mmol) was combined to give a yellow light suspension. After stirring at rt for 2 h, sodium triacetoxyborohydride (223 mg, 1.054 mmol) was added and the reaction was stirred for an additional 16 h. Finally, the reaction mixture was washed with NaHCO ₃ and brine, dried over MgSO ₄ and evaporated to give a light brown solid. The solid was triturated with EtOAc to give 7-cyclopentyl-2- [5- (1-dimethylamino-3-aza-bicyclo [3.1.0] hexane-3-carbonyl) -pyridin- -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (n) in 24% yield and> 90% purity.

Example 18

2-ylamino] -7H-pyrrolo [2,3-c] pyridin-2- d] pyrimidine-6-carboxylic acid dimethylamide

Step 1.

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -3,8-dihydro- Diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester.

Pyrimidin-2-ylamino) nicotinic acid (400 mg, 1.01 &lt; RTI ID = 0.0 &gt; mmol) was combined with 3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (250 mg, 1.18 mmol, 1.1 eq.) to give 3- [6- Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -3,8-diaza- bicyclo [3.2 .1] octane-8-carboxylic acid, which was used immediately in the next step without further purification.

Step 2.

2-ylamino] -7H-pyrrolo [2,3-c] pyridin-2- d] pyrimidine-6-carboxylic acid dimethylamide.

According to the deprotection method 1, 3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2- ylamino) -7-cyclopentyl-2- [5- (3,8-diaza-bicyclo [3.2.1] octane- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide as a white solid (0.290 g, 0.594 mmol) ) As a white solid in 59% yield.

Alternative procedure for Example 18.

2-ylamino] -7H-pyrrolo [2,3-c] pyridin-2- d] pyrimidine-6-carboxylic acid dimethylamide.

Step 1: Synthesis of 6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3-d] pyrimidin-2-ylamino) nicotinic acid.

To a solution of methyl 6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3-d] pyrimidin-2- ylamino) nicotinate (2.0 g, 4.9 mmol) was added 1M LiOH (aq) (6 mL, 1.2 eq) and the slurry was stirred at 45 &lt; 0 &gt; C for 12 h (the slurry became clear). After cooling to room temperature, the THF was evaporated and the reaction mixture was treated with 1 N HCl until pH = 1-2. The resulting precipitate was filtered, the filtrate was extracted with 20% isopropanol / CH ₂ Cl ₂ (3 x 100 mL) and the combined organic layers were dried, filtered and concentrated to give a tan solid. The tan solid was triturated with acetone to give the desired product as a tan solid (1.56 g, 73% yield) which was used without further purification.

Pyridin-2-ylamino) -pyridine-3-carbonyl] - 3 (1 H) -quinolin- , 8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester.

Pyrrolo [2,3-d] pyrimidin-2-ylamino) nicotinic acid (400 mg, 1.01 mmol) in DMF (5 mL) (HBTU, 580 mg, 1.53 mmol, 1.5 eq.) And N, N'-tetramethyluronium hexafluorophosphate (HBTU, Diisopropylethylamine (0.55 mL, 3.0 eq) was added and the resulting mixture was stirred at room temperature for 5 minutes. To the reaction mixture was added 3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (250 mg, 1.18 mmol, 1.1 eq.). The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted in EtOAc and 0.5M HCl, washed with water, dried over Na ₂ SO _4, filtered, and concentrated. The material was used immediately in the next step without further purification.

Step 3: Synthesis of the title compound.

CH ₂ Cl ₂ (4 mL) of 3- [6- (7-cyclopentyl-6-dimethylcarbamoyl -7H- pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridin -3 -Carbamoyl] -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (0.232 g, 1. mmol) in 4M HCl in dioxane 2.54 mL, 10.14 mmol, 10 eq.) At 25 &lt; 0 &gt; C. At 25 ℃ After stirring for 4 hours, the reaction mixture was filtered, and the CH ₂ Cl ₂ (5 mL). The residue was collected and dissolved in water, then basified with 1M NaOH and extracted with CH ₂ Cl ₂ (2 x 15 mL). The combined organic layers were dried over Na ₂ SO _4, filtered, and concentrated under reduced pressure to a tan solid. The crude material was purified by column chromatography (MeOH / CH ₂ Cl ₂ ) to give the desired product as a white solid (0.290 g, 0.594 mmol, 59%).

Example 19

Synthesis of 7-cyclopentyl-2- [5 - ((S, S) -2,5-diaza-bicyclo [2.2.1] heptane- 2- carbonyl) -pyridin- 2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Step 1.

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] - (S, S ) -2,5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester.

Pyrrolor2.3-dJpyrimidin-2-ylamino) nicotinic acid (0.150 g, 0.380 &lt; RTI ID = 0.0 &gt; mmol) was combined with (S, S) -2,5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert- butyl ester (100 mg, 0.504 mmol, 1.3 eq) - (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2- ylamino) -pyridine-3- carbonyl] - (S, Diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester, which was used directly in the next step.

Step 2.

Synthesis of 7-cyclopentyl-2- [5 - ((S, S) -2,5-diaza-bicyclo [2.2.1] heptane- 2- carbonyl) -pyridin- Lt; / RTI &gt; [2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Deprotection According to Method 1, 5- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2- ylamino) -pyridine- -2,5-diaza- bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester was reacted with 7-cyclopentyl-2- [5 - ((S, S -2,5-diaza- bicyclo [2.2.1] heptane-2-carbonyl) -pyridin- 2- ylamino] -7H-pyrrolo [2,3- d] pyrimidine- Acid dimethylamide as a white solid (55 mg, 0.110 mmol) in 29% yield.

Example 20

Pyrrolo [2,3-d] pyrimidin-2-yl] -pyridin- Pyrimidine-6-carboxylic acid dimethylamide

Pyrrolo [2,3-d] pyrimidin-2-yl] -pyridin- Pyrimidine-6-carboxylic acid dimethylamide.

According to general amide formation method 2, 6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3-d] pyrimidin- Yl) amino) nicotinic acid (88 mg, 0.146 mmol) was combined with octahydro-pyrrolo [1,2-a] pyrazine (0.050 mL, 0.264 mmol, 1.6 eq.) Followed by 7-cyclopentyl- 2-ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (100 mg, As a white solid (40 mg, 0.077 mmol) in 29% yield.

Example 21

Pyrrolo [2, 3-a] pyrazine-2-carbonyl) -pyridin-2- ylamino] -7H-pyrrolo [ 3-d] pyrimidine-6-carboxylic acid dimethylamide

Pyrrolo [2, 3-a] pyrazine-2-carbonyl) -pyridin-2- ylamino] -7H-pyrrolo [ 3-d] pyrimidine-6-carboxylic acid dimethylamide.

According to general amide formation method 2, 6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3-d] pyrimidin- Amino) nicotinic acid (100 mg, 0.165 mmol) was combined with (R) -octahydro-pyrrolo [1,2-a] pyrazine (40 mg, 0.317 mmol, 1.9 eq.) Followed by 7-cyclopentyl- Pyrrolo [2,3-d] pyrimidine (prepared according to the procedure described for the preparation of Example 1, step 2) from 5 - ((R) -hexahydro-pyrrolo [ -6-carboxylic acid dimethylamide as a white solid (60 mg, 0.113 mmol) in 69% yield.

Example 22

2-ylamino] -7H-pyrrolo [2,3-c] pyridin-2- d] pyrimidine-6-carboxylic acid dimethylamide

Step 1.

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -3,8-dihydro- Diaza-bicyclo [3.2.1] octane-3-carboxylic acid benzyl ester.

Pyrrolor2.3-dPyrimidin-2-ylamino) nicotinic acid (700 mg, 1.78 &lt; RTI ID = 0.0 &gt; mmol) was reacted with 3,8-diaza-bicyclo [3.2.1] octane-3-carboxylic acid benzyl ester (520 mg, 2.11 mmol, 1.2 equiv) (PCT international application, 2009067108, Pyridin-2-ylamino) -pyridin-3-yl] -pyridin-2-ylamino) -pyridin- Carbonyl] -3,8-diaza-bicyclo [3.2.1] octane-3-carboxylic acid benzyl ester as an off-white solid (550 mg, 0.839 mmol) in 47% yield.

Step 2.

2-ylamino] -7H-pyrrolo [2,3-c] pyridin-2- d] pyrimidine-6-carboxylic acid dimethylamide.

To a solution of 8- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3-d] pyrimidin- 2- ylamino) -pyridine- ] -3,8-diaza-bicyclo [3.2.1] octane-3-carboxylic acid benzyl ester (550 mg, 0.883 mmol) and 10% Pd / C (100 mg, 0.1 eq) Evacuated and purged with N ₂ , then recharged with hydrogen under balloon pressure and stirred for 16 hours. The reaction mixture was then filtered through a pad of celite and the filtrate was concentrated to a colorless oil. Ethyl acetate / heptane was added to the oil and the resultant precipitate was triturated to give 7-cyclopentyl-2- [5- (3,8-diaza-bicyclo [3.2.1] octane- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide as a white solid (260 mg, 0.532 mmol) in 60% yield.

Example 23

2-ylamino] -7H-pyrrolo [2,3-c] pyridin-2- d] pyrimidine-6-carboxylic acid methylamide.

Step 1.

Preparation of 3- (6-amino-pyridine-3-carbonyl) -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester.

2-Aminopyridyl-5-carboxylic acid (0.651 g, 4.71 mmol) was reacted with 3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert- Butyl ester (1.00 g, 4.71 mmol) followed by the addition of 3- (6-amino-pyridine-3-carbonyl) -3,8-diaza-bicyclo [3.2.1] octane- Acid tert-butyl ester as a white solid (0.780 g, 2.35 mmol) in 50% yield.

Step 2.

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -3,8- Diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid methylamide (see WO 2010020675) (0.150 g, 0.538 mmol Carboxylic acid tert-butyl ester (0.188 g, 0.565 mmol, 1.05 &lt; RTI ID = 0.0 &gt; Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] - 3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester as a yellow solid which was used directly in step 3.

Step 3.

2-ylamino] -7H-pyrrolo [2,3-c] pyridin-2- d] pyrimidine-6-carboxylic acid methylamide

Deprotection According to Method 1, 3- [6- (7-cyclopentyl-6-methylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2- ylamino) -pyridine- -7-cyclopentyl-2- [5- (3,8-diaza-bicyclo [3.2.1] octane- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid methylamide (60 mg, 0.126 mmol) was reacted with 24 % Yield.

Example 24

Synthesis of 7-cyclopentyl-2- [5 - ((S, S) -2,5-diaza-bicyclo [2.2.1] heptane- 2- carbonyl) -pyridin- 2,3-d] pyrimidine-6-carboxylic acid methylamide

Step 1.

Preparation of 5- (6-amino-pyridine-3-carbonyl) - (S, S) 2,5-diaza- bicyclo [2.2.1] heptane-2- carboxylic acid tert-butyl ester.

Aminopyridyl-5-carboxylic acid (0.697 g, 5.04 mmol) was reacted with (S, S) -2,5-diaza- bicyclo [2.2.1] heptane- -Carboxylic acid tert-butyl ester (1.00 g, 5.04 mmol, 1.0 eq) followed by the addition of 5- (6- amino-pyridine-3- carbonyl) -2,5- diaza- bicyclo [2.2 .1] heptane-2-carboxylic acid tert-butyl ester as a white solid (350 mg, 1.01 mmol) in 20% yield.

Step 2.

(1S, 4S) -5- [6- (7-cyclopentyl-6-methylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2- ylamino) -pyridine- ] -2,5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester

7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid methylamide (see WO 2010020675) (0.120 g, 0.431 mmol ) Was obtained in the same manner as (1S, 4S) -5- (6-amino-pyridine-3-carbonyl) -2,5- diaza- bicyclo [2.2.1] heptane- (1S, 4S) -5- [6- (7-cyclopentyl-6-methylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2- Amino) -pyridine-3-carbonyl] -2,5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester as a yellow solid. This material was used directly in step 3 below.

Step 3.

Heptane-2-carbonyl) -pyridin-2-ylamino] -7H-pyrrolo [2,3-c] 2, 3-d] pyrimidine-6-carboxylic acid methylamide

Deprotection According to Method 1, (lS, 4S) -5- [6- (7-cyclopentyl-6-methylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- -2,5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester was reacted with 7-cyclopentyl-2- [5 - ((1S, 4S -2,5-diaza- bicyclo [2.2.1] heptane-2-carbonyl) -pyridin- 2- ylamino] -7H-pyrrolo [2,3- d] pyrimidine- Acid methylamide (70 mg, 0.152 mmol) in 35% yield.

Example 25

Pyrrolo [2,3-c] azepine-7-carbonyl) -pyridin-2-ylamino] -7H-pyrrolo (2-oxo- [2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Step 1.

(3aR, 8aS) -7-Phenethyl-octahydro-pyrrolo [2,3-c] azepine- 1 -carboxylic acid benzyl ester.

To a solution of (3aR, 8aS) -7-phenethyl-decahydro-pyrrolo [2,3-c] azepine (4.0 g, 16.37 mmol) in ethyl acetate (100 mL) (PCT international application, 2005097791, 2005 (20 mL) was added a solution of potassium carbonate (6.79 g, 49.1 mmol, 3.0 eq) in water (100 mL). The biphasic solution was cooled to 0 C and then benzyl chloroformate (2.80 mL, 19.64 mmol, 1.2 eq.) Was added dropwise. The resulting mixture was stirred at 23 &lt; 0 &gt; C for 3 hours. The mixture was partitioned and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water followed by brine, the organic layer was dried (Na ₂ SO ₄ ), filtered and the filtrate was concentrated to give an orange oil. The crude material was purified using silica gel chromatography (1: 2 ethyl acetate / heptane -> 100% ethyl acetate -> 12: 1 CH ₂ Cl ₂ / methanol) to give (3aR, 8aS) -7-phenethyl- Pyrrolo [2,3-c] azepine-l-carboxylic acid benzyl ester.

Step 2.

(3aR, 8aS) -octahydro-pyrrolo [2,3-c] azepine-l-carboxylic acid benzyl ester.

To a solution of (3aR, 8aS) -7-phenethyl-octahydro- pyrrolo [2,3-c] azepine- 1 -carboxylic acid benzyl ester (1.0 g, 2.64 mmol) in 1,2-dichloroethane (20 mL) ) Was added 1-chloroethylcarbonochloridate (0.286 mL, 2.64 mmol, 1.0 eq.) At 0 &lt; 0 &gt; C. The reaction was stirred for 1 hour while warming to 23 &lt; 0 &gt; C and then refluxed for 3 hours. The solvent was removed in vacuo, then 20 mL of methanol was added and the reaction mixture was heated to 50 &lt; 0 &gt; C for 1 hour. The reaction was concentrated and purified using chromatography (1: 2 ethyl acetate / heptane -> 100% ethyl acetate -> 12: 1 CH ₂ Cl ₂ / methanol) to give (3aR, 8aS) -octahydro- pyrrolo [ 3-c] azepine-1-carboxylic acid benzyl ester.

Step 3.

Pyrrolo [2,3-c] azepine-7-carbonyl) -pyridin-2-ylamino] -7H-pyrrolo (2-oxo- [2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Pyrrolo [2,3-d] pyrimidin-2-ylamino) nicotinic acid (5 eq of lithium chloride) in DMF (3 mL) (0.088 g, 0.146 mmol), HBTU (0.086 mg, 0.226 mmol, 1.6 eq.) And triethylamine (0.100 mL, 0.717 mmol, 4.9 eq.) In DMF ) -Octahydro-pyrrolo [2,3-c] azepine-1 -carboxylic acid benzyl ester (0.040 mg, 0.146 mmol, 1.0 eq) was added and the reaction stirred at 23 <0> C for 1.5 h. The reaction mixture was diluted with ethyl acetate and the mixture was washed with 0.5 M HCl (aq) followed by water (3x), brine, the organic layer was dried (Na ₂ SO ₄ ), filtered and the filtrate was concentrated. The crude material was purified using chromatography (methanol / CH ₂ Cl ₂ ) to yield a white solid. To the resulting solid (42 mg) was added 10% Pd / C (15 mg) followed by methanol (5 mL). The suspension was covered with H ₂ balloons while stirring for 6 hours. The contents of the reaction were filtered through celite and the filtrate was concentrated to a white solid which was purified by trituration from ethyl acetate / heptane followed by chromatography (methanol / CH ₂ Cl ₂ mixture) to give 7-cyclo Pyrrolo [2,3-c] azepine-7-carbonyl) -pyridin-2-ylamino] -7H-pyrrolo [2,3- 3-d] pyrimidine-6-carboxylic acid dimethylamide. (20 mg, 0.039 mmol, 27%).

Example 26

2.2.1] heptane-2-carbonyl) pyridin-2-ylamino) -N, N-dihydro- Dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

Pyrrolo [2,3-d] pyrimidin-2-ylamino) nicotinic acid was prepared according to Method 3 for amide formation from (lR, 4R, 7R 2-azabicyclo [2.2.1] heptan-7-ol to obtain 7-cycloheptyl-2- (5 - ((1R, 4R, 7R) -7- Heptane-2-carbonyl) pyridin-2-ylamino) -N, N-dimethyl-7H- pyrrolo [2,3- d] pyrimidine- 6- carboxamide (47 mg, 78% yield) .

Example 27

Synthesis of 2- (5- (8-acetyl-3,8-diazabicyclo [3.2.1] octane-3-carbonyl) pyridin- Pyrrolo [2,3-d] pyrimidine-6-carboxamide

2,3-d] pyrimidin-2-ylamino) nicotinic acid was prepared according to Method 3 from 1- (3, &lt; RTI ID = (8-acetyl-3,8-diazabicyclo [3.2.1] octane-3-carbonyl) pyridin-2 -7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide (43 mg, 62% yield).

Example 28

Synthesis of 7-cyclopentyl-2- (5- (8- (2-hydroxyethyl) -3,8-diazabicyclo [3.2.1] octane-3-carbonyl) pyridin- Dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

2,3-d] pyrimidin-2-ylamino) nicotinic acid was prepared according to Method 3 for the amide formation from 2- (3, 8-dimethoxy- -Dihaabicyclo [3.2.1] octan-8-yl) ethanol to obtain 7-cyclopentyl-2- (5- (8- (2- hydroxyethyl) -3,8- diazabicyclo [3.2.1 Pyrrolo [2,3-d] pyrimidine-6-carboxamide (18 mg, 59% yield) was converted to the title compound .

Example 29

2-ylamino) -N, N-dimethyl-7H (5H) -quinolin- - pyrrolo [2,3-d] pyrimidine-6-carboxamide

To a solution of 2- (5- (3,8-diazabicyclo [3.2.1] octane-3-carbonyl) pyridin-2- ylamino) -7-cyclopentyl- To a solution of pyrrolo [2,3-d] pyrimidine-6-carboxamide (42 mg, 0.086 mmol) in acetone (0.6 ml) was added and the resulting reaction mixture was stirred at room temperature for 1 h. Na (AcO) ₃ BH (55 mg, 0.26 mmol) was added and the resulting reaction mixture was stirred overnight at room temperature. When LCMS indicated the reaction was complete, the reaction mixture was diluted with DCM and washed with saturated NaHCO ₃ (2X), brine. The combined aqueous layers were back-extracted with DCM and the combined organic layers were dried over Na ₂ SO ₄ , filtered and purified by column chromatography (0-20% MeOH / CHCl ₂ ) to give 7-cyclopentyl-2- ( N, N-dimethyl-7H-pyrrolo [2,3-c] pyridin- d] pyrimidine-6-carboxamide (64 mg, 88% yield).

Example 30

2.2.1] heptane-2-carbonyl) pyridin-2-ylamino) -N, N-dihydro- Dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

2,3-d] pyrimidin-2-ylamino) nicotinic acid was prepared according to Method 3 for amide formation from (lS, 4S, 5S 2-azabicyclo [2.2.1] heptan-5-ol to give 7-cyclopentyl-2- (5 - ((1S, 4S, 5S) -5- Heptane-2-carbonyl) -pyridin-2-ylamino) -N, N-dimethyl-7H- pyrrolo [2,3- d] pyrimidine- 6- carboxamide (40 mg, 63% yield) .

Example 31

2.2.1] heptane-2-carbonyl) pyridin-2-ylamino) -N, N-dihydro- Dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

2,3-d] pyrimidin-2-ylamino) nicotinic acid was reacted with (1S, 4S, 5R (3R) 2-azabicyclo [2.2.1] heptan-5-ol to give 7-cyclopentyl-2- (5 - ((1S, 4S, 5R) -5- Heptane-2-carbonyl) pyridin-2-ylamino) -N, N-dimethyl-7H- pyrrolo [2,3- d] pyrimidine-6- carboxamide (40 mg) .

Example 32

2-ylamino) -7H-pyrrolo [2,3-c] pyridin-2-ylmethyl) 3-d] pyrimidine-6-carboxamide

Step 1

pyrrolo [2,3-d] pyrimidin-2-ylamino) nicotinoyl) hexahydro-pyrrolo [2,3-d] pyrimidin- [3,4-c] pyrrole-2 (1H) -carboxylate

2,3-d] pyrimidin-2-ylamino) nicotinic acid was prepared according to Method 3 for amide formation from tert-butyl hexahydrophosphoric acid (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3-c] pyrrole- 3-d] pyrimidin-2-ylamino) nicotinoyl) hexahydropyrrolo [3,4-c] pyrrol-2 (1H) -carboxylate (45 mg) in 63% yield.

Step 2

2-ylamino) -7H-pyrrolo [2,3-c] pyridin-2-ylmethyl) 3-d] pyrimidine-6-carboxamide &lt; / RTI &gt;

According to the deprotection method 1, tert-butyl 5- (6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3- d] pyrimidin- (45 mg, 0.076 mmol) was reacted with 7-cyclopentyl-N, N-dimethyl-2- (5- (octanoyl) Pyrrolo [2,3- d] pyrimidine-6-carboxamide (18 mg) was reacted with 48 (4-chloropyridin-2-ylmethyl) % Yield.

Example 33

3-azabicyclo [3.2.1] octane-3-carbonyl) pyridin-2-ylamino) -N, Dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

3-azabicyclo [3.2.1] octane-3-carbonyl) pyridin-2-ylamino) -N, Dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

According to the general amide forming method 3, 6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3- d] pyrimidin-2-ylamino) nicotinic acid was dissolved in 3-azabicyclo (5R, 5S, 8r) -8-hydroxy-3-azabicyclo [ Pyrrolo [2,3-d] pyrimidine-6-carboxamide (50 mg) was reacted with 71 % Yield.

Example 34

2-ylamino) -N, N-dimethyl-7H-pyrrolo [2,3-c] Pyrrolo [2,3-d] pyrimidine-6-carboxamide

Step 1

Preparation of 3-benzyl-N, N-dimethyl-3-azabicyclo [3.2.1] octan-8-

Dimethylamine (2 ml, 1M in THF) was added to a solution of 3-benzyl-3-azabicyclo [3.2.1] octan-8-one (107 mg, 0.50 mmol) in DCM (2 ml) The reaction mixture was stirred at room temperature for 1 hour. Na (AcO) ₃ BH (316 mg, 1.49 mmol) was added and the reaction mixture was stirred overnight at room temperature. When TLC showed complete, the reaction mixture was diluted with DCM and washed with water and brine. The combined aqueous layers were back-extracted with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered, concentrated and purified by column chromatography to give 3-benzyl-N, N-dimethyl-3-azabicyclo [3.2.1] octan- 80 mg) in 67% yield.

Step 2

Preparation of N, N-dimethyl-3-azabicyclo [3.2.1] octane-8-amine

3-Azabicyclo [3.2.1] octan-8-amine (80 mg, 0.45 mmol) was dissolved in MeOH (10 ml) and the atmosphere was replaced with N ₂ Respectively. 10% Pd / C (catalytic amount) was added and the atmosphere was replaced with H ₂ (3X). The resulting reaction mixture was stirred overnight at room temperature under a balloon pressure. When the TLC no longer showed a UV active spot, Pd / C was filtered off (always kept wet with MeOH) and the filtrate was concentrated to give N, N-dimethyl-3-azabicyclo [3.2.1] 8-amine (44 mg) in 87% yield.

2-ylamino) -N, N-dimethyl-7H-pyrrolo [2,3-c] Pyrrolo [2,3-d] pyrimidine-6-carboxamide

2,3-d] pyrimidin-2-ylamino) nicotinic acid was prepared according to Method 3 for amide formation from N, N-dimethyl- Cyclopentyl-2- (5- (8- (dimethylamino) -3-azabicyclo [3.2.1] octane-3-carbonyl) Pyridin-2-ylamino) -N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine- 6- carboxamide (12 mg) in 14% yield.

Example 35

Synthesis of 7-cyclopentyl-2- (5- (8- (1 -hydroxypropan-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carbonyl) pyridin- ) -N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide

To a solution of 2- (5- (3,8-diazabicyclo [3.2.1] octane-3-carbonyl) pyridin-2- ylamino) -7-cyclopentyl-N, N-dimethyl Hydroxypropan-2-one (2 ml) was added to a solution of the resulting compound (105 mg, 0.22 mmol), and the resulting The reaction mixture was stirred for 1 hour at room temperature. Sodium triacetoxyborohydride was added and the reaction mixture was stirred at room temperature overnight. When TLC / LCMS showed complete, the reaction mixture was diluted with dichloromethane and washed with saturated NaHCO ₃ (2X) and brine. The combined aqueous layers were back-extracted with dichloromethane and the combined organic layers were dried over sodium sulfate, filtered, concentrated and purified by column chromatography (0-20% methanol / dichloromethane) to give 7-cyclopentyl- Diazabicyclo [3.2.1] octane-3-carbonyl) pyridin-2-ylamino) -N, N-dimethyl (4- -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide (39 mg, 33% yield).

Example 36

Dihydro-2- [5- (3,8-diaza-bicyclo [3.2.1] octane-3-carbonyl) Pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide

Step 1

7H-pyrrolo [2,3-d] pyrimidin-2-ylamino) -nicotinic acid methyl ester Manufacturing

According to general NC coupling procedure 1, 7-exo-bicyclo [2.2.1] hept-2-yl-2-chloro-7H- pyrrolo [2,3- d] pyrimidine- Amide (267 mg, 0.84 mmol) was combined with methyl 6-aminonicotinate (140 mg, 0.92 mmol) followed by the addition of 6- (7-exo-bicyclo [2.2.1] hept- - dimethylcarbamoyl-7H-pyrrolo [2,3-d] pyrimidin-2-ylamino) -nicotinic acid methyl ester (364 mg) was obtained and used as is without further characterization.

Step 2

Preparation of 6- (7-exo-bicyclo [2.2.1] hept-2-yl-6-dimethyl-carbamoyl-7H-pyrrolo [2,3- d] pyrimidin-

To a solution of 6- (7-exo-bicyclo [2.2.1] hept-2-yl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- -Ylamino) -nicotinic acid methyl ester (364 mg, 0.84 mmol) was added 5 ml of an aqueous solution of lithium hydroxide (176 mg, 4.19 mmol). The mixture was heated to 60 &lt; 0 &gt; C for 18 h, then cooled and then acidified to pH 4 using 6N hydrochloric acid. The resulting mixture was then diluted with water and extracted with 20% 2-propanol (3x) in chloroform solution. The organic layer was washed with brine then dried over anhydrous sodium sulfate, filtered and concentrated to give 6- (7-exo-bicyclo [2.2.1] hept-2-yl-6-dimethylcarbamoyl- 2,3-d] pyrimidin-2-ylamino) -nicotinic acid as a brown powder, which was used directly.

Step 3

Pyrrolo [2,3-d] pyrimidin-3-ylmethyl) -lH-pyrrolo [2,3-d] pyrimidin- 2-ylamino) -pyridine-3-carbonyl] -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

According to general amide formation method 1, the title compound was obtained from 6- (7-exo-bicyclo [2.2.1] hept-2-yl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- -Ylamino) -nicotinic acid (100 mg, 0.24 mmol) was combined with 3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert- butyl ester (61 mg, 0.29 mmol) Pyrrolo [2,3-d] pyrimidin-2-ylmethyl) -lH-pyrrolo [2,3-d] pyrimidin- 3-carbonyl] -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester, which was obtained directly without purification or further characterization Respectively.

Step 4

According to the deprotection method 2, 3- [6 - ((1R, 2R, 4S) -7-bicyclo [2.2.1] hept- 3-carbonyl] -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester was reacted with 7- ( (3, 8-diaza-bicyclo [3.2.1] octane-3-carbonyl) -pyridine- Ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (40 mg) in 33% yield.

Example 37

The title compound was prepared from 7- (4-tert-butyl-cyclohexyl) -2- [5- (3,8-diaza- bicyclo [3.2.1] - pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Step 1

Pyrrolo [2,3-d] pyrimidin-2-ylamino] -pyridine-3-carbaldehyde was prepared in accordance with the general method of example 1 from 3- {6- [7- (4- tert- butyl- cyclohexyl) -6-dimethylcarbamoyl- Carbonyl] -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

Pyrrolidine 2,3-d] pyrimidine-6-carboxylic acid dimethylamide (prepared according to general NC coupling procedure 1) from trans-7- (4-tert- butyl-cyclohexyl) -2-chloro-7H- 157 mg, 0.43 mmol) was combined with 3- (6-amino-pyridine-3-carbonyl) -3,8-diaza-bicyclo [3.2.1] octane- 8-carboxylic acid tert- Pyrrolo [2,3-d] pyrimidin-2-ylamino] -pyridine-lH-pyrrolo [2,3- d] pyrimidin- 3-carbonyl} -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester, which was used directly.

Step 2

(3,8-diaza-bicyclo [3.2.1] octane-3-carbonyl) -pyridin-2-ylamino] -pyridin- -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Deprotection According to Method 2, 3- {6- [7- (4-tert-butyl-cyclohexyl) -6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 3-carbonyl} -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester was reacted with trans-7- (4-tert- butyl-cyclohexyl Pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidin- 6-carboxylic acid dimethylamide (90 mg) in 37% yield.

Example 38

Synthesis of 7-cyclopentyl-2- [6- (3,8-diaza-bicyclo [3.2.1] octane-3-carbonyl) -pyridazin-3- ylamino] -7H-pyrrolo [2,3 d] pyrimidine-6-carboxylic acid dimethylamide

Step 1

Preparation of 3- (6-amino-pyridazine-3-carbonyl) -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester.

6-Amino-pyridazine-3-carboxylic acid (212 mg, 1.0 mmol) was reacted with 3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert -Butyl ester (139 mg, 1.0 mmol) to give 3- (6-amino-pyridazine-3-carbonyl) -3,8- diaza- bicyclo [3.2.1] octane-8-carboxylic acid tert -Butyl ester as a white solid (169 mg, 0.51 mmol) in 51% yield.

Step 2

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridazine-3-carbonyl] - 3,8-dihydro- -Diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester.

7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (98 mg, 0.336 mmol) was reacted with 3- 3-carbonyl) -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid terf-butyl ester (112 mg, 0.336 mmol) Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridazine-3-carbonyl] -3,8-diaza -Bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (115 mg, 0.195 mmol) in 58% yield.

Step 3

Synthesis of 7-cyclopentyl-2- [6- (3,8-diaza-bicyclo [3.2.1] octane-3-carbonyl) -pyridazin-3- ylamino] -7H-pyrrolo [2,3 -d] pyrimidine-6-carboxylic acid dimethylamide

Deprotection According to Method 2, 3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- Carboxylic acid tert-butyl ester (110 mg, 0.187 mmol) was added to a solution of 7-cyclopentyl-2- [6- (3,2,3,4-tetrahydroisoquinolin- Dihydro-8-diaza- bicyclo [3.2.1] octane-3-carbonyl) -pyridazin-3- ylamino] -7H- pyrrolo [2,3- d] pyrimidine- 6- carboxylic acid dimethylamide To a white solid (55 mg, 0.112 mmol) in 60% yield.

Example 39

Synthesis of 7-cyclopentyl-2- (5- (9-hydroxy-1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] -N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide

Synthesis of 7-cyclopentyl-2- (5- (9-hydroxy-1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] -N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide.

According to Method 1, 6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3-d] pyrimidin-2- ylamino) Niacin and 1,3,5-trimethyl-3,7-diazabicyclo [3.3.1] nonan-9-ol are combined to obtain 7-cyclopentyl-2- (5- (9- 2,3-d] pyrimidin-2-ylamino) -N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidin- 6-carboxamide (266 mg) was obtained in 68% yield.

Example 40

Diazabicyclo [3.3.1] nonane-9-carbonyl) pyridin-2-ylamino) -7-cyclopentyl-N, Dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

Step 1

Diazabicyclo [3.3.1] nonane-9-carbonyl) pyridin-2-ylamino) -7-cyclopentyl-N, Dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide.

According to general amide formation method 2, 6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3-d] pyrimidin- ) Nicotinic acid and (1R, 5S) -tert-butyl 3-oxa-7,9-diazabicyclo [3.3.1] nonane- - (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3-d] pyrimidin- Cyclo [3.3.1] nonane-7-carboxylate (115 mg) in 85% yield.

Step 2

Diazabicyclo [3.3.1] nonane-9-carbonyl) pyridin-2-ylamino) -7-cyclopentyl-N, Dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide.

Deprotection According to Method 2, (lR, 5S) -tert-butyl 9- (6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3- d] pyrimidin- 3-oxa-7,9-diazabicyclo [3.3.1] nonane-7-carboxylate was reacted with 2- (5 - ((1R, 5S) -3- Diazabicyclo [3.3.1] nonane-9-carbonyl) pyridin-2-ylamino) -7-cyclopentyl-N, -6-carboxamide (80 mg) in 83% yield.

Example 41

Cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-aza- / RTI &gt; d] pyrimidine-6-carboxamide

Step 1

pyrrolo [2,3-d] pyrimidin-2-ylamino) nicotinoyl) -2,6-dihydroquinolin- -Diazaspiro [3.3] heptane-2-carboxylate.

Amide A mixture of 6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3-d] pyrimidin-2- ylamino) -nicotinic acid (199 mg, 0.5 mmol, Butyl 6- (6- (7-cyclopentyl-piperazin-1-yl) -1H-pyrazole-3-carbaldehyde Pyrrolo [2,3-d] pyrimidin-2-ylamino) nicotinoyl) -2,6-diazaspiro [3.3] heptane-2-carboxylate As a white solid (214 mg, 0.37 mmol) in 74% yield.

Step 2

Cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-aza- -d] pyrimidine-6-carboxamide &lt; / RTI &gt;

Deprotection According to Method 2, tert-butyl 6- (6- (7- cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3- d] pyrimidin- Diazaspiro [3.3] heptane-2-carboxylate (120 mg, 0.21 mmol, 1.0 eq.) Was added to a solution of 2- (5- (2,6- Pyrrolo [2,3-d] pyrimidine-6-carboxamide (35 mg, 0.076 mmol) in tetrahydrofuran To 36% yield.

Example 42

3-aza-bicyclo [3.1.0] hexane-3-carbonyl) -pyridin-2- ylamino] -7-cyclopentyl- 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Step 1:

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridin-3,2-d] pyrimidin- -Carbonyl] -3-aza-bicyclo [3.1.0] hex-6-yl} -carbamic acid tert-butyl ester

Pyrrolor2.3-dPyrimidin-2-ylamino) -nicotinic acid (100 mg, 0.254 mmol) was prepared in accordance with the general method for amide formation method 1 from 6- (7-cyclopentyl-6-dimethylcarbamoyl- , 1.0 eq.) Was combined with (lS, 5R, 6S) - (3-aza- bicyclo [3.1.0] hex-6- yl) -carbamic acid tert- butyl ester (55.3 mg, 0.279 mmol, 1.1 equiv) Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridin-3,2-d] pyrimidin- -Carbonyl] -3-aza-bicyclo [3.1.0] hex-6-yl} -carbamic acid tert-butyl ester as an oil (165 mg) which was used directly without purification.

Step 2:

3-aza-bicyclo [3.1.0] hexane-3-carbonyl) -pyridin-2- ylamino] -7-cyclopentyl- 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

According to the deprotection method 2, {(lS, 5R, 6S) -3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- -Carbamoyl] -3-aza- bicyclo [3.1.0] hex-6-yl} -carbamic acid tert-butyl ester was reacted with 2- [5 - ((1S, 5R, 6S) 3-aza-bicyclo [3.1.0] hexane-3-carbonyl) -pyridin- 2-ylamino] -7-cyclopentyl-7H- pyrrolo [2,3- d] pyrimidine -6-carboxylic acid dimethylamide (76 mg) in 56% yield.

Example 43

Aza-bicyclo [3.2.1] octane-8-carbonyl) -pyridin-2-ylamino] -thiophene- -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Aza-bicyclo [3.2.1] octane-8-carbonyl) -pyridin-2-ylamino] -thiophene- -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Pyrrolor2.3-dPyrimidin-2-ylamino) -nicotinic acid (120 mg, 0.304 mmol) was prepared in accordance with the general method for amide formation method 1 from 6- (7-cyclopentyl-6-dimethylcarbamoyl- , 1.0 eq.) Was combined with (1S, 3S, 5R) -8-aza-bicyclo [3.2.1] octan- - ((1S, 3S, 5R) -3-hydroxy-8-aza-bicyclo [3.2.1] octane-8- carbonyl) -pyridin- 2- ylamino] -7H-pyrrolo [2,3 d] pyrimidine-6-carboxylic acid dimethylamide (110 mg) in 72% yield.

Example 44

Aza-bicyclo [3.2.1] octane-8-carbonyl) -pyridin-2-ylamino] -thiophene- -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Aza-bicyclo [3.2.1] octane-8-carbonyl) -pyridin-2-ylamino] -thiophene- -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

According to general amide formation method 1, 6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3-d] pyrimidin- 5R) -8-aza-bicyclo [3.2.1] octane-3-ol to obtain 7-cyclopentyl-2- [5 - ((1S, 3R, 5R) -3-hydroxy- 2-ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide was obtained in the form of a white solid.

Example 45

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- 2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- 2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Pyrrolor2.3-dPyrimidin-2-ylamino) -nicotinic acid (100 mg, 0.254 mmol) was prepared in accordance with the general method for amide formation method 1 from 6- (7-cyclopentyl-6-dimethylcarbamoyl- , 1.0 eq.) Was combined with 8-methyl-3,8-diaza-bicyclo [3.2.1] octane (55.5 mg, 0.279 mmol, 1.1 eq.) To give 7-cyclopentyl-2- [5- -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid &lt; EMI ID = Dimethylamide as a solid (77 mg) in 60% yield.

Example 46

3-carbonyl) -pyridin-2-ylamino] -7-cyclopentyl-7H-pyrrolo [2,3- - pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

3-carbonyl) -pyridin-2-ylamino] -7-cyclopentyl-7H-pyrrolo [2,3- -Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

According to general amide formation method 1, 6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin-2- ylamino) -nicotinic acid (200 mg, 0.507 mmol , 1.0 eq.) Was added to a solution of 3-benzyl-9-oxa-3,7-diaza-bicyclo [3.3.1] nonane (162 mg, 0.558 mmol, 1.1 equiv) (PCT International Application 2006137769, 3-carbonyl) -pyridin-2-ylamino] -7 (7-benzyl-9-oxa-3,7-diaza-bicyclo [3.3.1] - cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide as a solid (131 mg) in 39% yield.

Example 47

3-carbonyl) -pyridin-2-ylamino] -7H-pyrrolo [2,3-c] 2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Step 1:

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -9-oxa- Preparation of 3,7-diaza-bicyclo [3.3.1] nonane-3-carboxylic acid tert-butyl ester.

According to general amide formation method 1, 6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin-2- ylamino) -nicotinic acid (266 mg, , 1.0 eq.) Was combined with 9- oxa-3,7-diaza-bicyclo [3.3.1] nonane-3- carboxylic acid tert-butyl ester (100 mg, 0.438 mmol, 1.0 eq) Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -9-oxa- Diaza-bicyclo [3.3.1] nonane-3-carboxylic acid tert-butyl ester as a light pink powder (90 mg) in 34% yield.

Step 2:

3-carbonyl) -pyridin-2-ylamino] -7H-pyrrolo [2,3-c] 2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Deprotection According to Method 2, 7- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2- ylamino) -pyridine- -3,7-diaza-bicyclo [3.3.1] nonane-3-carboxylic acid tert-butyl ester was reacted with 7-cyclopentyl-2- [5- (9- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (prepared according to the procedure described for the synthesis of 15 mg) in 18% yield.

Example 48

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- d] pyrimidine-6-carboxylic acid dimethylamide.

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- d] pyrimidine-6-carboxylic acid dimethylamide.

Pyrrolor2.3-dPyrimidin-2-ylamino) -nicotinic acid (120 mg, 0.198 mmol) was reacted according to General Amide Formation Procedure 1 to give 6- (7-cyclopentyl-6-dimethylcarbamoyl- , 1.0 eq.) Was combined with 1,4-diaza-bicyclo [3.2.2] nonane (43.3 mg, 0.218 mmol, 1.1 eq.) To give 7-cyclopentyl-2- [5- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (25 mg) was added to a solution of 23 % Yield.

Example 49

Cyclopentyl-2- [5 - ((R, R) -2,5-diaza-bicyclo [2.2.1] heptane- 2- carbonyl) -pyridin- 2- ylamino] -7H- 2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Step 1:

Preparation of 5- (6-amino-pyridine-3-carbonyl) - (R, R) -2,5-diaza-bicyclo [2.2.1] heptane-2- carboxylic acid tert-butyl ester.

(R, R) -2,5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (1.0 g, 4.26 mmol, 1.0 eq) (6-amino-pyridine-3-carbonyl) - (R, R) -2,5-diaza-bicyclo [2.2. 1] heptane-2-carboxylic acid tert-butyl ester (420 mg, 31% yield).

Step 2:

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] - (R, R ) -2,5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester.

7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (200 mg, 0.683 mmol, 1.0 eq.) Was reacted according to general NC coupling procedure 1 (R, R) -2,5-Diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (217 mg, Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridin-3-yl] Carbonyl] - (R, R) -2,5-diaza-bicyclo [2.2.1] heptane-2- carboxylic acid tert- butyl ester (100 mg) in 25% yield.

Step 3:

Cyclopentyl-2- [5 - ((R, R) -2,5-diaza-bicyclo [2.2.1] heptane- 2- carbonyl) -pyridin- 2- ylamino] -7H- Lt; / RTI &gt; [2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Deprotection According to Method 2, 5- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2- ylamino) -pyridine- -2,5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester was reacted with 7-cyclopentyl-2- [5 - ((R, R -2,5-diaza- bicyclo [2.2.1] heptane-2-carbonyl) -pyridin- 2- ylamino] -7H-pyrrolo [2,3- d] pyrimidine- Was converted to the 22% yield with acid dimethylamide (20 mg).

Example 50

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- 2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Step 1:

(3- (6-Amino-2-methyl-pyridine-3-carbonyl) -3,8-diaza- bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester.

Diacetyl-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (279 mg, 1.31 mmol, 1.0 eq.) Was reacted with 6- amino-2- Methyl-nicotinic acid (200 mg, 1.31 mmol, 1.0 eq.) To give 3- (6-amino-2-methyl- -Carboxylic acid tert-butyl ester (400 mg) in 88% yield.

Step 2:

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -2-methyl-pyridine-3-carbonyl] - Preparation of 3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester.

7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (127 mg, 0.433 mmol, 1.0 eq.) Was reacted according to general NC coupling procedure 1 3-carbonyl) -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (180 mg, 0.520 mmol) , 1.2 eq.) To give 3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 3-carbonyl] -3,8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (70 mg) in 27% yield.

Step 3:

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- 2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Deprotection According to Method 2, 3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester was reacted with 7-cyclopentyl-2- [5- (3,8-diaza Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (prepared according to the procedure described for the synthesis of 36 mg) in 71% yield.

Example 51

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- 2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Step 1:

Preparation of 3- (6-amino-4-methyl-pyridine-3-carbonyl) -3,8-diaza- bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester.

Diacetyl-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (279 mg, 1.31 mmol, 1.0 eq.) Was reacted with 6-amino- Methyl-nicotinic acid (200 mg, 1.31 mmol, 1.0 eq.) To give 3- (6-amino-4-methyl- -Carboxylic acid tert-butyl ester (251 mg) in 55% yield.

Step 2:

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -4-methyl-pyridine-3-carbonyl] - Preparation of 3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester.

7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (140 mg, 0.479 mmol, 1.0 eq. ) Was reacted with 3- (6-amino-4-methyl-pyridine-3-carbonyl) -3,8-diaza-bicyclo [3.2.1] octane- Pyrrolo [2,3-d] pyrimidin-2-ylamino) -4-methyl-pyrimidin- 3-carbonyl] -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (114 mg) in 38% yield.

Step 3:

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- 2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Deprotection According to Method 2, 3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester was reacted with 7-cyclopentyl-2- [5- (3,8-diaza Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (prepared from 50 mg) in 57% yield.

Example 52

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- d] pyrimidine-6-carboxylic acid dimethylamide.

Step 1:

Preparation of 3-benzyl-3,9-diaza-bicyclo [3.3.1] nonane-9-carboxylic acid tert-butyl ester.

To a solution of 3-benzyl-3,9-diaza-bicyclo [3.3.1] nonane (755 mg, 3.49 mmol, 1.0 eq) in CH ₂ Cl ₂ (10 mL) was added di-tert-butyl carbonate 990 mg, 4.54 mmol, 1.3 eq.) And triethylamine (0.730 mL, 5.24 mmol, 1.5 eq.) Were added and the mixture was stirred at 23 &lt; 0 &gt; C for 16 h. The reaction mixture was diluted with CH ₂ Cl ₂ and washed with water. The organics were collected, dried (Na ₂ SO ₄ ), filtered and concentrated to an oil. The crude material was purified by silica gel chromatography eluting with an ethyl acetate / heptane mixture to give the desired product as a colorless oil (477 mg) in 41% yield.

Step 2:

Diaza-bicyclo [3.3.1] nonane-9-carboxylic acid tert-butyl ester.

Carboxylic acid tert-butyl ester (477 mg, 1.51 mmol, 1.0 eq.) And palladium hydroxide on carbon (466 mg, 1.0 eq.) In ethanol (10 mL) mg) was stirred under hydrogenation under balloon pressure until no more hydrogen was absorbed. The reaction was then filtered through celite and concentrated under reduced pressure. Diazabicyclo [3.3.1] nonane-9-carboxylic acid tert-butyl ester (170 mg) was obtained in 47% yield by purification using crude material (MeOH / ethyl acetate) .

Step 3:

Preparation of 3- (6-amino-pyridine-3-carbonyl) -3,9-diaza-bicyclo [3.3.1] nonane-9-carboxylic acid tert-butyl ester.

Diaza-bicyclo [3.3.1] nonane-9-carboxylic acid tert-butyl ester (170 mg, 0.751 mmol, 1.1 eq.) Was reacted with 6-amino-nicotinic acid 94 mg, 0.683 mmol, 1.0 eq.) Was combined with 3- (6-amino-pyridine-3-carbonyl) -3,9-diaza-bicyclo [3.3.1] nonane-9- Ester (170 mg) in 72% yield.

Step 4:

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -3,9-dihydro- Diaza-bicyclo [3.3.1] nonane-9-carboxylic acid tert-butyl ester.

7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.342 mmol, 1.0 eq) Carboxylic acid tert-butyl ester (130 mg, 0.376 mmol, 1.1 equiv) was added to a solution of 3- (6- amino-pyridine-3- carbonyl) -3,9- diaza- bicyclo [3.3.1] Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -3, Diaza-bicyclo [3.3.1] nonane-9-carboxylic acid tert-butyl ester (121 mg) in 59% yield.

Step 5:

Deprotection According to Method 2, 3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2- ylamino) -pyridine- -3,7-diazabicyclo [3.3.1] nonane-9-carboxylic acid tert-butyl ester was reacted with 7-cyclopentyl-2- [5- (3,9- diaza- bicyclo [ 3.3.1] nonane-3-carbonyl) -pyridin-2-ylamino] -7H-pyrrolo [2,3- d] pyrimidine-6- carboxylic acid dimethylamide (86 mg) Respectively.

Example 53

(3, 8-diaza-bicyclo [3.2.1] octane-3-carbonyl) -pyridin-2- ylamino] -7H- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Step 1:

Pyrrolo [2,3-d] pyrimidin-2-ylamino] -pyridine-3-carbaldehyde was prepared in accordance with the general method of example 1 from 3- {6- [7- (4- tert- butyl- phenyl) -6-dimethylcarbamoyl- Carbonyl] -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester.

Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.35 mmol) 0.280 mmol, 1.0 eq.) Was added to a solution of 3- (6-amino-pyridine-3-carbonyl) -3,8- diaza- bicyclo [3.2.1] octane- 8-carboxylic acid tert-butyl ester , 0.280 mmol, 1.0 eq.) To give 3- {6- [7- (4- tert -butyl-phenyl) -6-dimethylcarbamoyl- 7H- pyrrolo [2,3- d] pyrimidin- 2- -3-carbonyl} -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (112 mg) in 58% yield.

Step 2:

(3, 8-diaza-bicyclo [3.2.1] octane-3-carbonyl) -pyridin-2- ylamino] -7H- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Deprotection According to Method 2, 3- {6- [7- (4-tert-butyl-phenyl) -6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- (4-tert-butyl-phenyl) -2- (2-methyl-pyridin-3-carbonyl) -3,8- diaza- bicyclo [3.2.1] octane-8-carboxylic acid tert- Pyrrolo [2,3-d] pyrimidin-6-ylmethyl) -lH-pyrrolo [2,3-d] pyrimidin- Carboxylic &lt; / RTI &gt; acid dimethylamide (67 mg) (79%).

Example 54

3-carbonyl) -pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidin- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Step 1:

Pyrrolo [2,3-d] pyrimidin-2-ylamino] -pyridine-3-carbaldehyde was prepared in accordance with the general method of example 1 from 3- {6- [7- (3- tert- butyl- phenyl) -6-dimethylcarbamoyl- Carbonyl] -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester.

Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.35 mmol) 0.280 mmol, 1.0 eq.) Was added to a solution of 3- (6-amino-pyridine-3-carbonyl) -3,8- diaza- bicyclo [3.2.1] octane- 8-carboxylic acid tert-butyl ester , 0.280 mmol, 1.0 eq.) To give 3- {6- [7- (3- tert -butyl-phenyl) -6-dimethylcarbamoyl- 7H- pyrrolo [2,3- d] pyrimidin- 2- -3-carbonyl} -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (116 mg) in 60% yield.

Step 2:

3-carbonyl) -pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidin- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

According to the deprotection method 2, 3- {6- [7- (3-tert-butyl-phenyl) -6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- (3-tert-butyl-phenyl) -2- (4-methyl-pyridin-3-carbonyl) -3,8- diaza- bicyclo [3.2.1] octane-8-carboxylic acid tert- Pyrrolo [2,3-d] pyrimidin-6-ylmethyl) -lH-pyrrolo [2,3-d] pyrimidin- Carboxylic &lt; / RTI &gt; acid dimethylamide (75 mg) (89%).

Example 55

3-carbonyl) -pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidin- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Step 1:

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -3,8- Diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester.

General N-C Coupling According to procedure 1, 2-chloro-7-cyclobutyl-7H-pyrrolo [

3-d] pyrimidine-6-carboxylic acid dimethylamide (200 mg, 0.718 mmol, 1.0 eq.) Was reacted with 3- (6-amino- 3.2.1] octane-8-carboxylic acid terf-butyl ester (262 mg, 0.789 mmol, 1.1 eq.) To give 3- [6- (7-cyclobutyl- 6- methylcarbamoyl-7H- pyrrolo [ 2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -3,8-diaza- bicyclo [3.2.1] octane-8-carboxylic acid tert- mg, 50% yield).

Steps: 2

2-ylamino] -7H-pyrrolo [2,3-c] pyridin-2- d] pyrimidine-6-carboxylic acid dimethylamide.

Deprotection According to Method 2, 3- [6- (7-cyclobutyl-6-methylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2- ylamino) -pyridine- 3-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester was reacted with 7-cyclobutyl-2- [5- (3,8- diaza- bicyclo [ Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (128 mg) (74 mg, %).

Example 56

3-carbonyl) -pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidin- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Step 1:

Pyrrolo [2,3-d] pyrimidin-2-ylamino] - (3-methylsulfanyl) Pyridine-3-carbonyl} -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester.

7H-pyrrolo [2,3-d] pyrimidine-6-carbaldehyde was prepared using general Buchwald method 1, starting from 2-chloro-7- (1-cyclopropyl-piperidin- (95 mg, 0.273 mmol, 1.0 eq.) Was reacted with 3- (6-amino-pyridine-3-carbonyl) -3,8- diaza- bicyclo [3.2.1] octane-8- Butyl ester (100 mg, 0.300 mmol, 1.1 eq.) To give 3- {6- [7- (1 -cyclopropyl- piperidin- 4- yl) -6- dimethylcarbamoyl-7H- 2-ylamino] -pyridine-3-carbonyl} -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (131 mg, 71% yield).

Step 2:

2- [5- (3,8-diaza-bicyclo [3.2.1] octane-3-carbonyl) -pyridin-2-yl Amino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Deprotection According to Method 2, 3- {6- [7- (1 -cyclopropyl-piperidin-4-yl) -6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidine -3-carbonyl} -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester was reacted with 7- (1-cyclopropyl- Pyridin-2-ylamino] -7H-pyrrolo [2, 3-dihydro- , 3-d] pyrimidine-6-carboxylic acid dimethylamide (25 mg) (27%).

Example 57

2- [5- (3,8-diaza-bicyclo [3.2.1] octane-3-carbonyl) -pyridin-2- Ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Step 1:

Pyrrolo [2,3-d] pyrimidin-2-ylamino] -lH-pyrrolo [2,3-d] pyrimidin- -Pyridine-3-carbonyl} -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester.

2,3-d] pyrimidine-6-carbaldehyde according to general NC coupling procedure 1, starting from l- (l-tert- butylpiperidin- 3-carbonyl) -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylate Butyl ester (90 mg, 0.272 mmol, 1.1 eq.) To give 3- {6- [7- (l-tert- butyl- piperidin- 4- yl) -6- dimethylcarbamoyl- Pyrrolo [2,3-d] pyrimidin-2-ylamino] -pyridine-3-carbonyl} -3,8-diaza-bicyclo [3.2.1] octane- Ester (80 mg) in 47% yield.

Step 2:

2- [5- (3,8-diaza-bicyclo [3.2.1] octane-3-carbonyl) -pyridin-2- Ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

According to the deprotection method 2, 3- {6- [7- (1-tert-butyl-piperidin-4-yl) -6-dimethylcarbamoyl-7H- pyrrolo [2,3- 3-carbonyl} -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester was reacted with 7- (1-tert- butyl - 3-carbonyl) -pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidin- [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (42 mg) in 59% yield.

Example 58

2-ylamino] -7H-pyrrolo [2,3-a] pyrimidin- lt; / RTI &gt; d] pyrimidine-6-carboxylic acid dimethylamide.

Step 1:

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] - 3,8-dihydro- -Diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester.

Pyrrolidine 2,3-d] pyrimidine-6-carboxylic acid dimethylamide (150 mg, 0.534 mmol, 1.0 eq.) In accordance with the general NC coupling procedure 1, Carboxylic acid tert-butyl ester (178 mg, 0.534 mmol, 1.0 eq.) Was added to a solution of 3- (6-amino-pyridine- Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] - 3,8-Diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (189 mg) was obtained in 61% yield.

Step 2:

2-ylamino] -7H-pyrrolo [2,3-a] pyrimidin- lt; / RTI &gt; d] pyrimidine-6-carboxylic acid dimethylamide.

Deprotection According to Method 1, 3- [6- (7-tert-butyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- Butyl ester was prepared from 7-tert-butyl-2- [5- (3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert- Pyrido [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (80 mg) in 48% Yield.

Example 59

Diaza-bicyclo [3.2.1] octane-3-carbonyl] -pyridine (0.15 g) was added to a solution of 2- {5- [ Ylamino} -7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide

Step 1:

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridin-3-ylamino) Carbonyl] -3,8-diaza-bicyclo [3.2.1] octane-8-carbonyl} -3-methylsulfanyl-propyl) -carbamic acid tert-butyl ester

According to general amide formation method 1, 7-cyclopentyl-2- [5- (3,8-diaza-bicyclo [3.2.1] octane-3-carbonyl) -pyridin- (100 mg, 0.205 mmol, 1.0 eq.) Was combined with BOC-D-methionine (51 mg, 0.205 mmol, 1.0 eq.) To give the title compound as a pale yellow solid. Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl ] -3,8-diaza-bicyclo [3.2.1] octane-8-carbonyl} -3-methylsulfanyl-propyl) -carbamic acid tert-butyl ester (105 mg) .

Step 2:

Diaza-bicyclo [3.2.1] octane-3-carbonyl] -pyridine (0.15 g) was added to a solution of 2- {5- [ -2-ylamino} -7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide

According to the deprotection method 2, ((R) -1- {3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 3-carbonyl] -3,8-diaza-bicyclo [3.2.1] octane-8-carbonyl} -3-methylsulfanyl-propyl) -carbamic acid tert- - {5- [8 - ((R) -2-amino-4-methylsulfanyl-butyryl) -3,8- diaza- bicyclo [3.2.1] octane- 7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (60 mg, 91%).

Example 60

Bicyclo [3.2.1] octane-3-carbonyl] -pyridin-2-ylamino} -7-cyclopentyl -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Step 1:

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] - Diaza-bicyclo [3.2.1] oct-8-yl} -2-oxo-ethyl) -carbamic acid tert-butyl ester

According to general amide formation method 1, a mixture of 1,7-cyclopentyl-2- [5- (3,8-diaza-bicyclo [3.2.1] octane-3-carbonyl) -pyridin- (100 mg, 0.205 mmol, 1.0 eq.) Was combined with BOC-glycine (39.4 mg, 0.225 mmol, 1.1 eq.) To give (2 - {3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2- ylamino) -pyridine- Diaza-bicyclo [3.2.1] oct-8-yl} -2-oxo-ethyl) -carbamic acid tert-butyl ester (71 mg) in 53% yield.

Step 2:

Bicyclo [3.2.1] octane-3-carbonyl] -pyridin-2-ylamino} -7-cyclopentyl -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

According to the deprotection method 2, (2- {3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- Yl] -2-oxo-ethyl) -carbamic acid tert-butyl ester was reacted with 2- {5- [8- (2-amino-acetyl) -3,8-diaza- bicyclo [3.2.1] octane-3-carbonyl] -pyridin- 2- ylamino} -7-cyclopentyl- 3-d] pyrimidine-6-carboxylic acid dimethylamide (48 mg) in 89% yield.

Example 61

Cyclopentyl-2- {5- [8- (pyrrolidine-2-carbonyl) -3,8-diaza- bicyclo [3.2.1] octane- 3- carbonyl] -pyridin- Ylamino} -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Step 1:

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -3H-pyrrolo [2,3- , 8-diaza-bicyclo [3.2.1] octane-8-carbonyl} -pyrrolidine-1-carboxylic acid tert-butyl ester

According to general amide formation method 1, 7-cyclopentyl-2- [5- (3,8-diaza-bicyclo [3.2.1] octane-3-carbonyl) -pyridin- Pyrrolot [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.205 mmol, 1.0 eq) Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -3,8-diazolo [ -Acyclo [3.2.1] octane-8-carbonyl} -pyrrolidine-1-carboxylic acid tert-butyl ester (95 mg) in 64% yield.

Step 2:

Cyclopentyl-2- {5- [8- (pyrrolidine-2-carbonyl) -3,8-diaza- bicyclo [3.2.1] octane- 3- carbonyl] -pyridin- Ylamino} -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Deprotection According to Method 2, 2- {3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2- ylamino) -pyridine- 3-carbonyl] -3,8-diaza-bicyclo [3.2.1] octane-8-carbonyl} -pyrrolidine- 1- carboxylic acid tert- butyl ester was reacted with 7-cyclopentyl-2- { 3-carbonyl] -pyridin-2-ylamino} -7H-pyrrolo [2,3-d] pyrimidin- [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (36 mg) in 65% yield.

Example 62

3-methyl-butyryl) -3,8-diaza-bicyclo [3.2.1] octane-3-carbonyl] -pyridin-2 -Ylamino} -7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide

Step 1:

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridin-3-ylamino) Carbonyl] -3,8-diaza-bicyclo [3.2.1] octane-8-carbonyl} -2-methyl- propyl) -carbamic acid tert-butyl ester

According to general amide formation method 1, 7-cyclopentyl-2- [5- (3,8-diaza-bicyclo [3.2.1] octane-3-carbonyl) -pyridin- (60 mg, 0.123 mmol, 1.0 eq.) Was combined with BOC-D-valine (26.7 mg, 0.123 mmol, 1.0 eq.) To give the title compound as a colorless solid. Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl -3,8-diaza-bicyclo [3.2.1] octane-8-carbonyl} -2-methyl-propyl) -carbamic acid tert-butyl ester (82 mg) in 92% yield.

Step 2:

3-methyl-butyryl) -3,8-diaza-bicyclo [3.2.1] octane-3-carbonyl] -pyridin-2 -Ylamino} -7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide

According to the deprotection method 2, ((R) -1- {3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 3-carbonyl] -3,8-diaza-bicyclo [3.2.1] octane-8-carbonyl} -2-methyl- propyl) -carbamic acid tert- Diaza-bicyclo [3.2.1] octane-3-carbonyl] -pyridin-2-ylamino } -7-cyclopentyl-7H- pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (20 mg) in 28% yield.

Example 63

Synthesis of 7-cyclopentyl-2- [5- (8-methyl-d ₃ -3,8-diaza-bicyclo [3.2.1] Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Synthesis of 7-cyclopentyl-2- [5- (8-methyl-d ₃ -3,8-diaza-bicyclo [3.2.1] Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

To a solution of 7-cyclopentyl-2- [5- (3,8-diaza-bicyclo [3.2.1] octane-3-carbonyl) -pyridin-2- ylamino] -7H- To a mixture of pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (111 mg, 0.227 mmol, 1.0 eq.) And potassium carbonate (37.7 mg, 0.273 mmol, 1.2 eq.) Was added iodomethane- ₃ (0.021 mL, 0.341 mmol, 1.5 eq.) Was added and the mixture was stirred at 23 &lt; 0 &gt; C for 5 h. The reaction mixture was diluted with ethyl acetate and water, collected the organic portion, dried (Na ₂ SO _4), filtered, and concentrated. The residue was purified by chromatography (ethyl acetate / heptane) to give the desired product (15 mg) in 12% yield.

Example 64

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -3,8-dihydro- Diaza-bicyclo [3.2.1] octane-8-carboxylic acid ethyl ester

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -3,8-dihydro- Diaza-bicyclo [3.2.1] octane-8-carboxylic acid ethyl ester

CH ₂ Cl ₂ (5 mL) of 7-Cyclopentyl-2- [5- (3,8- diaza-bicyclo [3.2.1] octane-3-carbonyl) -pyridin-2-ylamino] To a solution of 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.205 mmol, 1.0 eq.) And diisopropylethylamine (0.071 mL, 0.409 mmol, 2.0 eq) Was added ethyl chloroformate (0.022 mL, 0.225 mmol, 1.1 eq) diluted to 3.0 mL of CH ₂ Cl ₂ . The reaction mixture was stirred at 23 &lt; 0 &gt; C for 1 hour and then diluted with water. Collect the organic portion, dried over Na ₂ SO _4, filtered, and concentrated. The crude reaction product was purified by silica gel chromatography to give 3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 3-carbonyl] -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid ethyl ester (25 mg) in 21% yield.

Example 65

2-ylamino) -N, N-dimethyl-7- (tetrahydro-2H-pyran-3-ylmethyl) -Yl) -7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide

Step 1

pyrrolo [2,3-d] pyrimidin-2-yl (4-fluorobenzyl) Amino) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate

Pyrrolidin-2-yl] pyrimidin-6-yloxy) -acetic acid ethyl ester was prepared according to general NC coupling procedure 1 from 2-chloro-N, N-dimethyl-7- (tetrahydro- Carboxamide (80 mg, 0.26 mmol) was reacted with tert-butyl 3- (6-aminicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8- carboxylate (82 mg, 0.26 mmol ) To give tert-butyl 3- (6- (6- (dimethylcarbamoyl) -7- (tetrahydro-2H-pyran-3- yl) -7H- pyrrolo [2,3- d] pyrimidin- 2-ylamino) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (40 mg) in 25% yield.

Step 2

2-ylamino) -N, N-dimethyl-7- (tetrahydro-2H-pyran-3-ylmethyl) -Yl) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

Deprotection According to Method 1, tert-butyl 3- (6- (6- (dimethylcarbamoyl) -7- (tetrahydro-2H-pyran-3- yl) -7H- pyrrolo [2,3- d (35 mg, 0.058 mmol) was reacted with 2- (5- (3, 8) -tetrahydro-2-pyridinylmethyl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane- Pyridin-2-ylmethyl) -7H-pyrrolo [3,2-d] azabicyclo [3.2.1] octane-3-carbonyl) 2,3-d] pyrimidine-6-carboxamide in 37% yield as the free base form (11 mg).

Example 66

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- d] pyrimidine-6-carboxylic acid dimethylamide

Step 1

Preparation of 2-chloro-7-cyclohexyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide

According to the general procedure A, 2-chloro-7-cyclohexyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide was synthesized (2.4 g, 17% overall yield).

Step 2

Preparation of 6- (7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3-d] pyrimidin-2-ylamino) -nicotinic acid methyl ester.

7-cyclohexyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (800 mg, 2.61 mmol) was reacted with 6- amino -Nicotinic acid methyl ester (397 mg, 2.61 mmol) was coupled with methyl 6- (7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- Ester (720 mg, 1.70 mmol) in 65% yield.

Step 3

Preparation of 6- (7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3-d] pyrimidin-2-ylamino) -nicotinic acid. Pyridin-2-ylamino) -nicotinic acid methyl ester (860 mg, 2.04 mmol) in THF (5 mL) To 25 mL of a solution of water and MeOH (2: 2: 1) was added solid LiOH (244 mg, 10.2 mmol). After stirring at 50 &lt; 0 &gt; C for 90 minutes, the reaction was acidified to pH 6 using 1M HCl and then partitioned into two phases using a mixture of water, isopropyl alcohol and chloroform. Removal of the organic layer and concentration afforded 805 mg (1.97 mmol) of 6- (7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- ) In 97% yield.

Step 4

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -3,8-dihydro- Diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester. To 1 mL of a DMF solution of 6- (7-cyclohexyl-6-dimethylcarbamoyl) -7H-pyrrolo [2,3- d] pyrimidin-2- ylamino) -nicotinic acid (50 mg, (32 mg, 0.043 mmol) and HBTU (49 mg, 0.129 mmol). After stirring at room temperature for 15 minutes, 3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (31.2 mg, 0.147 mmol) was added and the reaction mixture was stirred at room temperature Stirred for 4 hours. The reaction was quenched by pouring into brine and extracted with EtOAc. The organic extracts were dried with Na ₂ SO _4, filtered, and concentrated. The crude product was purified by NP-LC (Analogics, 10% MeOH in EtOAc) to give 3- [6- (7-cyclohexyl-6-dimethylcarbamoyl-7H- pyrrolo [ 3-carbonyl] -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (60 mg, 0.10 mmol) Respectively.

Step 5

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- d] pyrimidine-6-carboxylic acid dimethylamide.

Deprotection According to Method 2, 3- [6- (7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- Butyl ester (105 mg, 0.174 mmol) was added to a solution of 7-cyclohexyl-2- [5- (3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (78 &lt; RTI ID = 0.0 & mg, 0.155 mmol) in 89% yield.

Example 67

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- d] pyrimidine-6-carboxylic acid dimethylamide

Step 1

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyrimidine-5-carbonyl] -2,5-dihydro- -Diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester

Pyrimidin-2-ylamino) -nicotinic acid (50 mg, 0.122 mmol) was prepared in accordance with the general method for amide formation method 1 from 6- (7-cyclohexyl-6-dimethylcarbamoyl- ) Was combined with 2,5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (29.1 mg, 0.147 mmol) to obtain 5- [2- (7-cyclohexyl- Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyrimidine-5-carbonyl] -2,5-diaza- bicyclo [2.2.1] heptane- -Carboxylic acid tert-butyl ester (60 mg, 0.102 mmol) in 84% yield.

Step 2

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- d] pyrimidine-6-carboxylic acid dimethylamide.

Deprotection According to Method 2, 5- [2- (7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2- ylamino) -pyrimidin- -2,5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (110 mg, 0.187 mmol) was added to a solution of 7-cyclohexyl- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (prepared by reacting 5-diaza-bicyclo [2.2.1] heptane- 78 mg, 0.160 mmol) in 86% yield.

Example 68

2- [5- (3,8-diaza-bicyclo [3.2.1] octane-8-carbonyl) -pyridin-2-yl Amino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Step 1

Pyrrolo [2,3-d] pyrimidin-2-ylamino} - pyrimidin-4- 3-carbonyl) -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester.

According to general NC coupling procedure 1, 2-chloro-7- [4- (cyano-dimethyl-methyl) -phenyl-7H- pyrrolo [2,3- d] pyrimidine- 6- carboxylic acid dimethylamide (70 mg, 0.190 mmol) was reacted with 3- (6-amino-pyridine-3-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert- 0.190 mmol) was combined with 3- (6- {7- [4- (cyano-dimethyl-methyl) -phenyl] -6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- -3-carbonyl) -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid terf-butyl ester (63 mg, 0.095 mmol) in 50% yield .

Step 2

2- [5- (3,8-diaza-bicyclo [3.2.1] octane-8-carbonyl) -pyridin-2-yl Amino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Deprotection According to Method 2, 3- (6- {7- [4- (cyano-dimethyl-methyl) -phenyl] -6- dimethylcarbamoyl-7H- pyrrolo [2,3- d] pyrimidine Carboxylic acid terf-butyl ester (63 mg, 0.095 mmol) was added to a solution of 7- (2-amino-pyridin-3-carbonyl) -3,8-diaza-bicyclo [3.2.1] octane- - [5- (3,8-diaza-bicyclo [3.2.1] octane-8-carbonyl) -pyridin-2- ylamino] Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (48 mg, 0.085 mmol) in 89% yield.

Example 69

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- d] pyrimidine-6-carboxylic acid dimethylamide

Step 1

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -3,9-dihydro- Diaza-bicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester

Pyrimidin-2-ylamino) nicotinic acid (0.2 g, 0.507 &lt; RTI ID = 0.0 &gt; mmol) was combined with 3,9-diaza-bicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester (0.136 g, 0.6 mmol) to give 3- [6- (7-cyclopentyl- Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -3,9-diaza-bicyclo [4.2.1] -Carboxylic acid tert-butyl ester (0.269 g, 0.433 mmol) in 85% yield.

Step 2

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- d] pyrimidine-6-carboxylic acid dimethylamide

According to the deprotection method 1, 3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2- ylamino) Carboxylic acid tert-butyl ester (0.24 g, 0.398 mmol) was added to a solution of 7-cyclopentyl-2- [5- (3,9 Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (203 &lt; RTI ID = 0.0 & mg, 0.363 mmol) in 91.4% yield.

Example 70

Dihydro-7-carbonyl) -pyridin-2-ylamino] -7H-pyrrolo [2,3-c] 2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Step 1

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -3-oxa-quinolin- Preparation of 7,9-diaza-bicyclo [3.3.1] nonane-9-carboxylic acid benzyl ester.

Pyrimidin-2-ylamino) nicotinic acid (406 mg, 1.03 &lt; RTI ID = 0.0 &gt; mmol) was combined with 3-oxa-7,9-diaza-bicyclo [3.3.1] nonane-9-carboxylic acid benzyl ester (266 mg, 0.9 mmol) to give 7- [6- (7- Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -3-oxa-7,9-diaza- bicyclo [3.3 .1] nonane-9-carboxylic acid benzyl ester (0.466 g, 0.723 mmol) in 80% yield.

Step 2

Dihydro-7-carbonyl) -pyridin-2-ylamino] -7H-pyrrolo [2,3-c] 2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] - Carboxylic acid benzyl ester (0.461 g, 0.722 mmol), methanol ethyl acetate (12 ml), THF (3 ml), methanol (3 ml) and C phase Pd / 10%. The mixture was placed under a hydrogen balloon and stirred overnight. The mixture was purged with nitrogen and then methylene chloride was added. The resulting mixture was filtered through a pad of celite. The celite was washed with additional methylene chloride. The organic portion was combined and concentrated to a residue. The residue was purified by silica gel chromatography to obtain 7-cyclopentyl-2- [5- (3-oxa-7,9-diaza-bicyclo [3.3.1] nonane-7- carbonyl) -pyridine- Ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (338 mg, 0.67 mmol) in 93% yield.

Examples 71-72

Pyridin-2-ylamino] -7H-pyrrolo [2, &lt; / RTI &gt; 3-d] pyrimidine-6-carboxylic acid dimethylamide was purified by SFC chromatography using Chiralpak AD-H (Chiral Technologies), 21.2 x 250 mm, 5 [mu] m, 10% methanol, CO _2, 75 g / min flow rate, by chiral separation by SFC Thar purified -80 systems, performed with retention times of 2.5 min example 71, 7-cyclopentyl -2- [5 - ((1S, 6R) Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid &lt; EMI ID = Dimethylamide and a retention time of about 3.3 minutes. Example 2 Synthesis of 7-cyclopentyl-2- [5 - ((1R, 6S) -3,9- diaza- bicyclo [4.2.1] Carbonyl) -pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide.

Example 71

Synthesis of 7-cyclopentyl-2- [5 - ((1S, 6R) -3,9-diaza-bicyclo [4.2.1] 2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Example 72

Synthesis of 7-cyclopentyl-2- [5 - ((1R, 6S) -3,9-diaza-bicyclo [4.2.1] 2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Example 73

Synthesis of 7-cyclopentyl-2- [6- (3,8-diaza-bicyclo [3.2.1] octane-3-carbonyl) -pyridazin-3- ylamino] -7H-pyrrolo [2,3 d] pyrimidine-6-carboxylic acid dimethylamide

Step 1

Preparation of 3- (6-amino-pyridazine-3-carbonyl) -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester. Diazabicyclo [3.2.1] octane-8-carboxylic acid tert (tert-butoxycarbonylamino) -Butyl ester (139 mg, 1.0 mmol), HATU (456 mg, 1.2 mmol) and N, N-diisopropylethylamine (0.52 mL, 3.0 mmol). The mixture was stirred at room temperature overnight, a white solid (169 diluted with EtOAc, washed by brine, dried over Na ₂ SO _4, concentrated, purified using 0-20% MeOH / DCM on a silica normal mg, 0.51 mmol).

Step 2

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridazine-3-carbonyl] - 3,8-dihydro- -Diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester. To a 4 mL microwave vial was added a solution of 2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide (98 mg, 0.336 mmol) -Carbamic acid tert-butyl ester (112 mg, 0.336 mmol), BINAP (10.5 mg, 0.017 mmol) in THF _{), Cs 2 CO 3 (164} mg, 0.504 mmol) and _{Pd (OAc) 2 (3.8 mg} , 0.017 mmol) to Were added together. The tube was capped and then purged three times with N ₂ . Dioxane (1.68 mL) was added and the capped tube was heated in a microwave reactor to 120 &lt; 0 &gt; C for 20 minutes. After cooling, the reaction mixture was diluted with heptane to give a precipitated crude product. The crude product was isolated by filtration, resuspended in water, and subjected to vigorous stirring and sonication. After isolation by filtration, the product was purified by normal silica chromatography using a 0- &gt; 20% MeOH / EtOAc gradient to give a light tan solid (115 mg, 0.195 mmol).

Step 3:

Synthesis of 7-cyclopentyl-2- [6- (3,8-diaza-bicyclo [3.2.1] octane-3-carbonyl) -pyridazin-3- ylamino] -7H-pyrrolo [2,3 -d] pyrimidine-6-carboxylic acid dimethylamide.

To a solution of 3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3-d] pyrimidin- 2- ylamino) -pyridazine (1 mL, 13.0 mmol) was added to a solution of 3-amino-3- carbonyl] -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert- butyl ester (110 mg, Was added. After warming to room temperature and stirring for 1 hour, the reaction was concentrated under reduced pressure. The resulting oily residue was dissolved in 2 mL of MeOH and flushed through a PL-HCO ₃ MP-resin cartridge to remove TFA and then purified by HPLC to yield a white solid (55 mg, 0.112 mmol).

Example 74

3-aza-bicyclo [3.2.1] octane-3-carbonyl) -pyridin-2- ylamino] -7H-pyrrolo [2,3 d] pyrimidine-6-carboxylic acid dimethylamide

3-aza-bicyclo [3.2.1] octane-3-carbonyl) -pyridin-2- ylamino] -7H-pyrrolo [2,3 -d] pyrimidine-6-carboxylic acid dimethylamide

Pyrimidin-2-ylamino) nicotinic acid (528 mg, 1.34 &lt; RTI ID = 0.0 &gt; (8-oxa-3-aza-bicyclo [3.2.1] octane) was combined with 8-oxa-3-aza- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (213 mg, 0.435 mmol) was dissolved in 32.5 % Yield.

Example 75

Synthesis of 7-cyclopentyl-2- [5- (8-oxa-3,10-diaza-bicyclo [4.3.1] decane- 3-carbonyl) -pyridin- 2- ylamino] -7H-pyrrolo [ 2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Step 1

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -8-oxa- Preparation of 3,10-diaza-bicyclo [4.3.1] decane-10-carboxylic acid tert-butyl ester

Pyrrolor2.3-d] pyrimidin-2-ylamino) nicotinic acid (385 mg, 0.97 &lt; RTI ID = 0.0 &gt; mmol) was combined with 8-oxa-3,10-diaza-bicyclo [4.3.1] decane-10-carboxylic acid tert-butyl ester (215 mg, 0.887 mmol) to give 3- [6- Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -8-oxa-3,10-diaza- bicyclo [4.3.1] decane-10-carboxylic acid tert-butyl ester (323 mg, 0.522 mmol) in 59% yield.

Step 2

Synthesis of 7-cyclopentyl-2- [5- (8-oxa-3,10-diaza-bicyclo [4.3.1] decane- 3-carbonyl) -pyridin- 2- ylamino] -7H-pyrrolo [ 2,3-d] pyrimidine-6-carboxylic acid dimethylamide

According to the deprotection method 1, 3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2- ylamino) Butyl ester (313 mg, 0.506 mmol) was added to a solution of 7-cyclopentyl-2- [5- (4-fluorophenyl) Pyrrolo [2,3-d] pyrimidin-2-ylamino) -lH-pyrrolo [2,3-d] pyrimidin- -Carboxylic acid dimethylamide (187 mg, 0.35 mmol) in 69.1% yield.

Example 76

Dihydro-2- [5- (3,8-diaza-bicyclo [3.2.1] octane-3-carbonyl) Pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide

Step 1

Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide was purified by SFC chromatography, eluting with a solution of diisopropylphosphine Chiral separation by chiral separation by Ralpack AD-H (Chiral Technologies), 21.2 x 250 mm, 5 袖 m, 10% methanol, 100 mbar CO ₂ , 75 g / min flow rate, Thar SFC purification -80 system and enantiomer 1: 7- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (enantiomer 1 2-yl) -2-chloro-7H-pyrrolo [2,3-d] pyrimidin- -6-carboxylic acid dimethylamide (enantiomer 2 retention time 2.4 min).

Step 2

Pyrrolo [2,3-d] pyrimidin-3-ylmethyl) -lH-pyrrolo [2,3-d] pyrimidin- 2-ylamino) -pyridine-3-carbonyl] -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

According to general NC coupling procedure 1, 1,7- (1R, 2R, 4S) -bicyclo [2.2.1] hept-2-yl-2-chloro-7H- pyrrolo [2,3- 6-carboxylic acid dimethylamide (90 mg, 0.28 mmol) was reacted with 3- (6-amino-pyridine-3-carbonyl) -3,8- diaza- bicyclo [3.2.1] octane- Carboxylic acid tert-butyl ester (99 mg, 0.30 mmol) to give 3- [6 - ((lR, 2R, 4S) -7- bicyclo [2.2.1] hept- Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -3,8-diaza- bicyclo [3.2.1] octane- The acid tert-butyl ester was obtained and used as is without further characterization.

Step 3

Synthesis of 7- (1R, 2R, 4S) -bicyclo [2.2.1] hept-2-yl-2- [5- (3,8-diazabicyclo [3.2.1] octane- -2-ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

According to the deprotection method 2, 3- [6 - ((1R, 2R, 4S) -7-bicyclo [2.2.1] hept- 3-carbonyl] -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester was reacted with 7- ( (3, 8-diaza-bicyclo [3.2.1] octane-3-carbonyl) -pyridine- 2-ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (15 mg) to a total yield of 10%.

Example 77

(3S, 2S, 4R) -bicyclo [2.2.1] hept-2-yl-2- [5- (3,8- diaza- bicyclo [ Pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide

Step 1

Pyrrolo [2,3-d] pyrimidin-4-ylmethyl) - (2-methylsulfanyl) 2-ylamino) -pyridine-3-carbonyl] -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

(1S, 2S, 4R) -bicyclo [2.2.1] hept-2-yl-2-chloro-7H-pyrrolo [2,3- b] pyridine was prepared in accordance with the general NC coupling- d] pyrimidine-6- carboxylic acid dimethylamide (90 mg, 0.28 mmol) was reacted with 3- (6-amino-pyridine-3- carbonyl) -3,8- diaza- bicyclo [3.2.1] -8-carboxylic acid terf-butyl ester was prepared in a manner similar to that described in Example 1 to give 3- [6 - ((lS, 2S, 4R) -7-bicyclo [2.2.1] hept- Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridine-3-carbonyl] -3,8-diaza-bicyclo [3.2.1] octane- The ester was obtained and used as is without further characterization.

Step 2

(3S, 2S, 4R) -bicyclo [2.2.1] hept-2-yl-2- [5- (3,8- diaza- bicyclo [ Pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide

According to the deprotection method 2, 3- [6 - ((1S, 2S, 4R) -7-bicyclo [2.2.1] hept- 3-carbonyl] -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester was reacted with 7- ( (3, 8-diaza-bicyclo [3.2.1] octane-3-carbonyl) -pyridine- 2-ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide and after purification the title compound (5 mg) was obtained in 3% overall yield.

Example 78

2-ylamino] -7-cyclopentyl-7H-pyrrolo [2,3- b] pyridin- d] pyrimidine-6-carboxylic acid dimethylamide

Step 1

Preparation of [3- (6-nitro-pyridin-3-yl) -3-aza- bicyclo [3.1.0] hex-1-yl] -carbamic acid tert-butyl ester

5-Bromo-2-nitropyridine (50 mg, 0.246 mmol) was reacted with tert-butyl 3-azabicyclo [3.1.0] hexan-1-ylcarbamate (48.8 mg, 0.246 mmol) was combined with 75 mg of [3- (6-nitro-pyridin-3-yl) -3-aza- bicyclo [3.1.0] hex- 1 -yl] -carbamic acid tert- .

Step 2

Preparation of [3- (6-Amino-pyridin-3-yl) -3-aza- bicyclo [3.1.0] hex-1-yl] -carbamic acid tert-butyl ester

_{MeOH-CH 2 Cl 2 (3} : 1) of [3- (6-nitro-pyridin-3-yl) -3-aza-bicyclo [3.1.0] hex-1-yl] -carbamic acid tert- butyl Ester (150 mg, 0.468 mmol) in DMF (5 mL) was added Pd / C (24.92 mg, 0.234 mmol). The resulting mixture was stirred under H ₂ balloon (H ₂ / three times of vacuum exchange) at room temperature for 4 hours. LCMS showed complete conversion. The reaction mixture was then filtered through a pad of celite using DCM and concentrated to give a black precipitate. The precipitate was diluted in ethyl acetate and then filtered. The filtrate was then evaporated to give 120 mg of [3- (6-amino-pyridin-3-yl) -3-aza-bicyclo [3.1.0] hex- 1 -yl] -carbamic acid tert- % Yield.

Step 3

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridin-3-yl] -3-aza- Bicyclo [3.1.0] hex-1-yl} -carbamic acid tert-butyl ester

3-aza-bicyclo [3.1.0] hex-1-yl] -carbamic acid tert-butyl ester (120 mg, , 0.413 mmol) was combined with 2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide (121 mg, 0.413 mmol) Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridin-3-yl] -3-aza-bicyclo [3.1 -Hex-hex-1-yl} -carbamic acid tert-butyl ester in 89% yield.

Step 4

2-ylamino] -7-cyclopentyl-7H-pyrrolo [2,3- b] pyridin- d] pyrimidine-6-carboxylic acid dimethylamide

Deprotection According to Method 1, {3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2- ylamino) -pyridin- 3-aza-bicyclo [3.1.0] hex-1-yl} -carbamic acid tert-butyl ester 2- [5- 3-yl) -pyridin-2-ylamino] -7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide.

Example 79

Synthesis of 7-cyclopentyl-2- [6- (4-oxo-3,9-diaza-bicyclo [4.2.1] non-3-yl) pyridazin- , 3-d] pyrimidine-6-carboxylic acid dimethylamide

Step 1

Preparation of 2-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide

To a suspension of 2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide (2.93 g, 10 mmol) in 50 mL dioxane was added benzophenone imine the addition of g, 10.5 mmol), Pd ( OAc) 2 (0.11 g, 0.5 mmol), BINAP (0.31 g, 0.5 mmol) and _{Cs 2 CO 3 (4.89 g,} 15 mmol) , followed by purging the flask with N ₂ . The tube was then sealed and the mixture was heated at 120 &lt; 0 &gt; C for 1 hour. To the suspension was then added heptane and filtered. The precipitate was extracted with DCM and the extract was purified by SiO ₂ column chromatography to give 2- (benzhydrylidene-amino) -7- (1-ethyl-butyl) -7H-pyrrolo [ Pyrimidine-6-carboxylic acid dimethylamide (3.5 g, 8.0 mmol, 80% yield).

Step 2

Preparation of 2-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide

To a solution of 2- (benzhydrylidene-amino) -7- (l-ethyl-butyl) -7H-pyrrolo [2,3- d] pyrimidine- 6- carboxylic acid dimethylamide (3.5 g, 8.0 mmol) in anhydrous THF (20 mL) was added aqueous 2M HCl (1.32 mL) and the mixture was stirred for 20 minutes. To this was added 60 mL of heptane: EtOAc (4: 1 v / v) and 60 mL of aqueous 0.5 N HCl and the layers were separated. The acidic aqueous layer was basified to pH 10 with aqueous 25% NaOH solution and extracted again with EtOAc. Then, The organic extracts were washed with brine, dried (Na ₂ SO ₄₎ and concentrated and, SiO ₂ column chromatography (EtOAc in 0-20% MeOH) to give 2-amino-7-cyclopentyl-through -7H -Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide as a white solid (1.68 g, 6.15 mmol, 77% yield).

Step 3

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridazin-3-yl] -4-oxo- Synthesis of 3,9-diaza-bicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester

To a suspension of 3,6-dibromo-pyridazine (400 mg, 1.68 mmol) in 8 mL toluene in a dry pressure tube was added 4-oxo-3,9-diaza- bicyclo [4.2.1] (324 mg, 1.345 mmol), Pd ₂ (dba) ₃ (154 mg, 0.168 mmol), xanthex (195 mg, 0.336 mmol) and NaOt- Bu (242 mg, 2.52 mmol) was added and the suspension was bubbled with N ₂ for 3 min. The tube was then sealed and the mixture was heated at 100 &lt; 0 &gt; C for 3 hours. The seal was then opened and an additional amount of Pd ₂ (dba) ₃ (41 mg, 0.045 mmol), xanthophos (52 mg, 0.091 mmol), NaOt-Bu (65 mg, 0.680 mmol) Amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide (124 mg, 0.453 mmol). The mixture was heated again at 100 &lt; 0 &gt; C for 16 h, and the suspension was filtered through a celite plug and washed with 10% MeOH in DCM. The collected filtrates were combined and purified by two successive SiO ₂ columns to give 3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- Carboxylic acid tert-butyl ester (66 mg, 0.112 mmol, 8 &lt; RTI ID = 0.0 &gt; % Yield) as a white solid.

Step 4

Synthesis of 7-cyclopentyl-2- [6- (4-oxo-3,9-diaza-bicyclo [4.2.1] non-3-yl) pyridazin- , 3-d] pyrimidine-6-carboxylic acid dimethylamide

Deprotection According to Method 1, 3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2- ylamino) -pyridazin- Carboxylic acid tert-butyl ester (60 mg, 0.10 mmol) was reacted with 7-cyclopentyl-2- [6- (4-oxo-3,9-diaza-bicyclo [4.2.1] non-3-yl) pyridazin-3- ylamino] -7H- pyrrolo [2,3- d] pyrimidin- Carboxylic acid dimethylamide (9 mg, 0.018 mmol) in 18% yield.

Example 80

3-yl) -pyridin-2-ylamino] -7H-pyrrolo [2, 3-dihydro- , 3-d] pyrimidine-6-carboxylic acid dimethylamide

Step 1

Preparation of 3- (6-Nitro-pyridin-3-yl) -2-oxo-3,8-diaza- bicyclo [3.2.1] octane-8-carboxylic acid tert-

Following general NC coupling procedure 1, 5-bromo-2-nitropyridine (110 mg, 0.542) was reacted with 2-oxo-3,8-diaza- bicyclo [3.2.1] octane- butyl ester (135 mg, 0.596 mg) and purified by silica gel chromatography to give 3- (6-nitro-pyridin-3-yl) -2-oxo-3,8- diaza- bicyclo [ 3.2.1] octane-8-carboxylic acid tert-butyl ester (290 mg, 81%), MS m / z 349.0 (MH ⁺ ), was used directly without further characterization.

Step 2

Preparation of 3- (6-amino-pyridin-3-yl) -2-oxo-3,8-diaza- bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester.

Nitrogen Reduction According to procedure 1, 3- (6-Nitro-pyridin-3-yl) -2-oxo-3,8-diaza- bicyclo [3.2.1] Carboxylic acid tert-butyl ester (290 mg, 0.83 mmol) was combined with nitrogen and then 10% palladium on charcoal (200 mg, excess) was added. Purged with hydrogen and allowed to stir under a hydrogen atmosphere for 16 hours. Purged with nitrogen, filtered through a pad of celite, and washed with methanol. Concentration in vacuo afforded 146 mg &lt; RTI ID = 0.0 &gt; (6-amino-pyridin-3-yl) -2-oxo-3,8-diaza- bicyclo [3.2.1] octane-8-carboxylic acid tert- , 60%). Used without further purification.

Step 3

3-yl) -pyridin-2-ylamino] -7H-pyrrolo [2, 3-dihydro- , 3-d] pyrimidine-6-carboxylic acid dimethylamide tert-butyl ester.

According to general NC coupling procedure 1, 3- (6-amino-pyridin-3-yl) -2-oxo-3,8-diaza- bicyclo [3.2.1] octane- Butyl ester (146 mg, 0.46 mmol) was combined with 2-chloro-7-cycloheptyl-7H-pyrrolo [2,3- d] pyrimidine-6- carboxylic acid dimethylamide (134 mg, 0.42 mmol) -3-yl) -pyridin-2-ylamino] -7H-pyrrolo [2,3-c] 2,3-d] pyrimidine-6-carboxylic acid dimethylamide tert-butyl ester was obtained and used directly without further characterization.

Step 4

3-yl) -pyridin-2-ylamino] -7H-pyrrolo [2, 3-dihydro- , 3-d] pyrimidine-6-carboxylic acid dimethylamide.

According to the deprotection method 2, 7-cycloheptyl-2- [5- (2-oxo-3,8-diaza-bicyclo [3.2.1] oct- -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide tert-butyl ester was reacted with 7-cycloheptyl-2- [5- (2-oxo-3,8-diaza- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (100 mg) in 48% yield according to a procedure similar to that used for the synthesis of . &Lt; / RTI &gt;

Example 81

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- d] pyrimidine-6-carboxylic acid dimethylamide

Step 1

Preparation of cis-tert-butyl 5- (6-nitropyridin-3-yl) -4-oxohexahydropyrrolo [3,4-c] pyrrol-2 (1H) -carboxylate.

According to general NC coupling procedure 1, 5-bromo-2-nitropyridine (4.71 g, 23.2 mmol, 1.05 eq.) Was added to cis-tert- butyl 4-oxohexahydropyrrolo [3,4- 2 (1H) -carboxylate (5 g, 22.1 mmol, 1.0 eq.) Was combined and purified by silica gel, and then cis-tert- butyl 5- (6-nitropyridin- [3,4-c] pyrrol-2 (1H) -carboxylate (6.3 g) was obtained in 81% yield.

Step 2

Preparation of cis-tert-butyl 5- (6-aminopyridin-3-yl) -4-oxohexahydropyrrolo [3,4-c] pyrrol-2 (1H) -carboxylate.

Nitro group reduction According to the procedure 1, the title compound was obtained from cis-tert-butyl 5- (6-nitropyridin-3-yl) -4-oxohexahydropyrrolo [3,4- (1.05 g, 3.01 mmol.) Was reacted with cis-tert-butyl 5- (6-aminopyridin-3- yl) -4-oxohexahydropyrrolo [3,4- c] pyrrol- 0.0 &gt; (1.0 &lt; / RTI &gt; g).

Step 3

Pyrrolo [2,3-d] pyrimidin-2-ylamino) pyridin-3-yl) -acetic acid tert- -4-oxohexahydropyrrolo [3,4-c] pyrrol-2 (1H) -carboxylate.

Pyrido [2,3-d] pyrimidine-6-carboxamide (50.4 mg, 0.157 mmol) was reacted with 2-chloro-7-cycloheptyl- 3,4-c] pyrrol-2 (1H) -carboxylate (50 mg, 0.157 mmol, prepared from cis-tert- butyl 5- (6-aminopyridin- 1.0 eq.), Followed by silica gel chromatography to give cis-tert-butyl 5- (6- (7-cycloheptyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3- d] pyrimidine Pyridin-3-yl) -4-oxohexahydropyrrolo [3,4-c] pyrrol-2 (1H) -carboxylate (90 mg) in 94% yield.

Step 4

Pyrrol-2 (1H) -yl) pyridin-2-ylamino) - (5-methyl- 7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide.

According to the deprotection method 2, 7-cycloheptyl-N, N-dimethyl-2- (5- (cis-1-oxohexahydropyrrolo [3,4- c] pyrrol- Ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide was obtained in 85% yield after purification (64 mg).

Step 5

Pyrrol-2 (1H) -yl) pyridin-2-ylamino) - (5-methyl- 7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide (56 mg) and cis-racemic compound were separated by chiralpak® AS-H chiral column. The separated mobile phase was 30% MeOH containing 0.2% DEA. Two peaks were collected. The faster moving enantiomers were collected as enantiomer-2 (25 mg, 43% yield) as enantiomer-1 (23 mg, 38% yield) and the slower moving enantiomer.

Example 82

3,4-c] pyrrol-2 (1H) -yl) pyridin-2-ylmethyl) -2- Ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide. Enantiomer-1

Example 83

Pyrrol-2 (1H) -yl) pyridin-2-ylmethyl) -2- (5 - ((3aR, 6aS) Ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide. Enantiomer-2

Example 84

(1H) -yl) pyridin-2-ylamino) -7H-pyrrolo [2,3-c] pyridin- - pyrrolo [2,3-d] pyrimidine-6-carboxamide

Step 1

(1H) -yl) pyridin-2-ylamino) -7H-pyrrolo [2,3-c] pyridin- - pyrrolo [2,3-d] pyrimidine-6-carboxamide

According to general NC coupling procedure 1, 2-chloro-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3- d] pyrimidine- - (6-aminopyridin-3-yl) -4-oxohexahydropyrrolo [3,4-c] pyrrol-2 (1H) -carboxylate and then cis- Pyrrolo [2,3-d] pyrimidin-2-ylamino) pyridin-3-yl) -4-oxohexahydro pyrrolo [ 3,4-c] pyrrol-2 (1H) -carboxylate carboxylate (82 mg) in 89% yield.

Step 2

Deprotection According to Method 2, 7-cyclopentyl-N, N-dimethyl-2- (5-cis-1-oxohexahydropyrrolo [3,4- c] pyrrol- 2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide (61 mg) was obtained in 90% yield.

Step 3

(1H) -yl) pyridin-2-ylamino) -7H-pyrrolo [2,3-c] pyridin- -Pyrrolo [2,3-d] pyrimidine-6-carboxamide (52 mg) was isolated by chiralpak® AS-H chiral column. The separated mobile phase was 35% MeOH containing 0.2% DEA. Two peaks were collected. The faster moving enantiomers were collected as enantiomer-1 (15 mg, 29% yield) and the slower moving enantiomers as enantiomer-2 (18 mg, 34% yield).

Example 85

Pyrrol-2 (1H) -yl) pyridin-2-ylmethyl] -2- (5 - ((3aS, 6aR) -oxohexahydropyrrolo [3,4- Ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide. Enantiomer-1

Example 86

Pyrrol-2 (1H) -yl) pyridin-2-ylmethyl] -2- (5 - ((3aR, 6aS) Ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide. Enantiomer-2

Example 87

Pyrrolo [2,3-d] pyrimidin-2-ylamino) pyridin-3-yl) -acetic acid tert- Oxohexahydro-lH-pyrrolo [3,4-c] pyridin-2 (3H) -carboxylate

Step 1

LH-pyrrolo [3,4-c] pyridin-2 (3H) -carboxylate

According to general NC coupling procedure 1, 5-bromo-2-nitropyridine and cis-tert-butyl 6-oxohexahydro-lH-pyrrolo [3,4- c] pyridin-2 (3H) Yl) -lH-pyrrolo [3,4-c] pyridin-2 (3H) -carboxylate (1.0 g) was obtained in 85% yield.

Step 2

Preparation of cis-tert-butyl 5- (6-aminopyridin-3-yl) -6-oxohexahydro-lH-pyrrolo [3,4-c] pyridine-2 (3H) -carboxylate.

Pyrido [3,4-c] pyridin-2 (3H) - 1 H-pyrrolo [2,3-c] pyridin- Carboxylate (300 mg) in 96% yield.

Step 3

(6H, 7H, 7aH) -yl) pyridine prepared in Step 1 of Example 1 was used in the same manner as in Reference Example 1, except that 7-cycloheptyl-N, N-dimethyl- -2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide.

According to general NC coupling procedure 1, 2-chloro-7-cycloheptyl-N, N-dimethyl-7H-pyrrolo [2,3- d] pyrimidine- 3,4-c] pyridin-2 (3H) -carboxylate, which was then subjected to purification using cis-tert-butyl 5 Pyridin-2-ylamino) pyridin-3-yl) -6-oxohexahydro- -LH-pyrrolo [3,4-c] pyridin-2 (3H) -carboxylate (85 mg) in 86% yield.

Step 4

(6H, 7H, 7aH) -yl) pyridine prepared in Step 1 of Example 1 was used in the same manner as in Reference Example 1, except that 7-cycloheptyl-N, N-dimethyl- -2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide.

According to the deprotection method 2, 7-cycloheptyl-N, N-dimethyl-2- (5- (cis-6-oxotetrahydro-lH-pyrrolo [3,4- c] pyridin- Pyrrolo [2,3-d] pyrimidine-6-carboxamide (64 mg) in 89% yield.

Step 5

(6H, 7H, 7aH) -yl) pyridine prepared in Step 1 of Example 1 was used in the same manner as in Reference Example 1, except that 7-cycloheptyl-N, N-dimethyl- Pyrrolo [2,3-d] pyrimidine-6-carboxamide (56 mg) and cis-racemic compound were separated by chiralpak AD-H chiral column. The separated mobile phase was 35% MeOH containing 0.2% DEA. Two peaks were collected. Enantiomers that migrate faster were enantiomer-2 (16 mg, 28% yield) as enantiomer-1 (16 mg, 28% yield) and the slower moving enantiomer. The absolute stereochemistry was not determined.

Example 88

(6H, 7H, 7aH) -yl) pyridine prepared in Step 1 of Example 1 was used in the same manner as in Reference Example 1, except that 7-cycloheptyl-N, N-dimethyl- Ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide. Enantiomer-1

Example 89

(6H, 7H, 7aH) -yl) pyridine prepared in Step 1 of Example 1 was used in the same manner as in Reference Example 1, except that 7-cycloheptyl-N, N-dimethyl- Ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide. Enantiomer-2.

Example 90

Step 1

Pyridin-5 (6H, 7H, 7aH) -yl) pyridine prepared in Step 1 of Example 1 was used instead of 4- Ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

According to general NC coupling procedure 1, 2-chloro-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3- d] pyrimidine- 3,4-c] pyridin-2 (3H) -carboxylate, which was then subjected to purification using cis-tert-butyl 5 Pyridin-2-ylamino) pyridin-3-yl) -6-oxohexahydro- -LH-pyrrolo [3,4-c] pyridin-2 (3H) -carboxylate (81 mg) in 86% yield.

Step 2

According to the deprotection method 2, 7-cyclopentyl-N, N-dimethyl-2- (5- (cis-6-oxotetrahydro-lH-pyrrolo [3,4- c] pyridin- Pyrrolo [2,3-d] pyrimidine-6-carboxamide (64 mg) in 86% yield.

Step 3

Pyridin-5 (6H, 7H, 7aH) -yl) pyridine prepared in Step 1 of Example 1 was used instead of 4- 2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide (56 mg) and the cis racemic compound were chiral separated by chiralpak AD-H chiral column. The separated mobile phase was 40% IPA containing 0.2% DEA. Two peaks were collected. Enantiomers that migrate faster were enantiomer-2 (17 mg, 30% yield) as enantiomer-1 (16 mg, 28% yield) and as a slower moving enantiomer. The absolute stereochemistry was not determined.

Example 91

Pyridin-5 (6H, 7H, 7aH) -yl) pyridine prepared in Step 1 of Example 1 was used instead of 4- Ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

Example 92

Pyridin-5 (6H, 7H, 7aH) -yl) pyridine prepared in Step 1 of Example 1 was used instead of 4- Ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

Example 93

LH-pyrrolo [3,4-c] pyridin-5 (6H, &lt; RTI ID = 0.0 & 7H, 7aH) -yl) pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine- 6- carboxamide.

LH-pyrrolo [3,4-c] pyridin-5 (-yl) -pyridin-2-ylamine in THF (2.0 mL) Pyrrolo [2,3-d] pyrimidine-6-carboxamide (from Example 89, Enantiomer-2) (66 mg, , 0.128 mmol, 1 eq.) In toluene (5 mL) was added a 37% aqueous solution of formaldehyde (0.048 mL, 0.639 mmol, 5 eq). The reaction mixture was stirred at room temperature for 5 minutes. Solid sodium triacetoxyhydroborate (81 mg, 0.383 mmol, 3 eq.) Was added to the mixture. The reaction was stirred for an additional 10 min, quenched with 1 drop of TFA and neutralized with ammonia in methanol. The residue was concentrated in vacuo and purified by column chromatography (NH ₃ / MeOH / CH ₂ Cl ₂ ) to give 7-cycloheptyl-N, N-dimethyl- 2- (5 - ((3aS, 7aR) (6H, 7H, 7aH) -yl) pyridin-2-ylamino) -7H-pyrrolo [2,3- d] pyrimidine-6-carboxamide (67 mg) in quantitative yield.

Example 94

N, N-dimethyl-2- (5 - ((1R, 3R, 5S) -2 '-oxo-8- azaspiro [bicyclo [3.2.1] octane- 3-yl) pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine- 6- carboxamide.

Step 1

Pyrrolo [2,3-d] pyrimidin-2-ylamino (2-oxo-pyridin-2-yl) ) Pyridin-3-yl) -2'-oxo-8-azaspiro [bicyclo [3.2.1] octane-3,5'-oxazolidine] -8-carboxylate.

3-yl) -8-azaspiro [bicyclo [3.2.1] octane-3, 5 ' Oxo-pyridin-2-one (0.350 g, 0.935 mmol, 1.0 eq.) Was reacted with 2-chloro-7-cyclohexyl-7H- pyrrolo [2,3- d] pyrimidine- (0.287 g, 0.935 mmol, 1.0 eq.) To give (lR, 3r, 5S) -tert-butyl 3 '- (6- (7- , 3-d] pyrimidin-2-ylamino) pyridin-3-yl) -2'-oxo-8-aza spiro [bicyclo [3.2.1] octane-3,5'-oxazolidine] -Carboxylate (0.454 g) in 75% yield.

Step 2:

N, N-dimethyl-2- (5 - ((1R, 3R, 5S) -2 '-oxo-8- azaspiro [bicyclo [3.2.1] octane- Pyridin-3-yl) pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

According to the deprotection method 1, (1R, 3R, 5S) -tert-butyl 3 '- (6- (7- Yl) -2'-oxo-8-azaspiro [bicyclo [3.2.1] octane-3,5'-oxazolidine] -8-carboxylate 0.450 g, 0.713 mmol) was added to a solution of 7-cyclohexyl-N, N-dimethyl-2- (5 - ((1R, 3R, 5S) -2 ' -oxo-8- azaspiro [bicyclo [ Pyrido [2,3-d] pyrimidine-6-carboxamide (0.286 g, 0.517 mmol) To 73% yield.

Example 95

3,4-c] pyrrol-2 (1H) -yl) -5-methyl-1-oxohexahydro pyrrolo [3,4- Pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

According to General Reduction Alkylation Method 1, 7-cyclopentyl-N, N-dimethyl-2- (5 - ((3as, 6aR) -5-methyl-1-oxohexahydropyrrolo [3,4- -2 (lH) -yl) pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide.

Example 96

Step 1

4- (6-Nitropyridin-3-yl) -1,4-diazabicyclo [3.2.2]

According to general NC coupling procedure 1, 5- bromo-2-nitropyridine and 1,4-diazabicyclo [3.2.2] nonan-3-one are combined to give 4- (6-nitropyridin- -1,4-diazabicyclo [3.2.2] nonan-3-one (418 mg) in 64% yield.

Step 2

4- (6-aminopyridin-3-yl) -1,4-diazabicyclo [3.2.2]

Nitro group Reduction According to the procedure 1, 4- (6-aminopyridin-3-yl) -1,4-diazabicyclo [3.2.2] nonan-3-one (322 mg) was obtained in 88% yield.

Step 3

Synthesis of 7-cyclopentyl-N, N-dimethyl-2- (5- (3-oxo-1,4-diazabicyclo [3.2.2] Lt; / RTI &gt; [2,3-d] pyrimidine-6-carboxamide

According to general NC coupling procedure 1, 4- (6-aminopyridin-3-yl) -1,4-diazabicyclo [3.2.2] Dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide to obtain 7-cyclopentyl-N, N-dimethyl- Pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide was obtained in 86% yield Respectively.

Example 97

(3-oxo-1,4-diazabicyclo [3.2.2] nonan-4-yl) pyridin-2-ylamino) -7H-pyrrolo [ Lt; / RTI &gt; [2,3-d] pyrimidine-6-carboxamide

According to general NC coupling procedure 1, 2-chloro-7-cycloheptyl-N, N-dimethyl-7H-pyrrolo [2,3- d] pyrimidine- 3-yl) -1,4-diazabicyclo [3.2.2] nonan-3-one was used to synthesize 7-cycloheptyl-N, N-dimethyl- Pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide (103 mg) .

Example 98

Pyridin-2-ylamino] -7H-pyrrolo [2,3-a] pyrimidin- lt; / RTI &gt; d] pyrimidine-6-carboxylic acid dimethylamide.

Step 1:

Preparation of 2- (6-nitro-pyridin-3-yl) -hexahydro-pyrrolo [1,2-a] pyrazin-

1-one (0.202 g, 1.44 mmol) was reacted with 5-bromo-2-nitropyridine (0.293 g, 1.44 mmol, Pyridin-3-yl) -hexahydro-pyrrolo [1,2-a] pyrazin-1-one was obtained as a tan solid (0.170 g, 0.616 mmol) .

Step 2:

Pyridin-3-yl) -hexahydro-pyrrolo [1,2-a] pyrazin-1-one

Nitro-pyrrolo [1,2-a] pyrazin-1-one (0.170 g, 0.648 mmol) was reacted with 2- ( Pyridin-3-yl) -hexahydro-pyrrolo [1,2-a] pyrazin-1-one and was isolated in 84% yield as a yellow solid (0.126 g, 0.542).

Step 3:

Pyridin-2-ylamino] -7H-pyrrolo [2,3-a] pyrimidin- d] pyrimidine-6-carboxylic acid dimethylamide

Pyrrol-1, 2-a] pyrazin-1-one (0.050 g, 0.215 mmol) was reacted with 2- (6-amino- Cyclohexyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (0.066 g, 0.215 mmol, 1.0 eq) Pyrrolo [2,3-d] pyrimidine-6-carboxylate (prepared according to the procedure described for the synthesis of Acid dimethylamide as a beige solid (75 mg, 0.139 mmol) in 65% yield.

Example 99

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- lt; / RTI &gt; d] pyrimidine-6-carboxylic acid dimethylamide.

Step 1:

Preparation of 2- (6-nitro-pyridin-3-yl) -hexahydro-pyrido [1,2-a] pyrazin-

According to general NC coupling procedure 1, hexahydro-pyrido [1,2-a] pyrazin-1-one (0.300 g, 1.945 mmol) was reacted with 5-bromo-2-nitropyridine (0.395 g, 1.945 mmol, 1-one (0.481 g, 1.567 mmol) was obtained in 81% yield in a yield of 81% .

Step 2:

Preparation of 2- (6-amino-pyridin-3-yl) -hexahydro-pyrido [1,2-a] pyrazin-

Nitro group Reduction According to procedure 1, 2- (6-nitro-pyridin-3-yl) -hexahydro-pyrido [1,2- a] pyrazin-1-one (0.200 g, 0.724 mmol) 1-one (0.170 g, 0.690 mmol) was converted to 95% yield.

Step 3:

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- -d] pyrimidine-6-carboxylic acid dimethylamide.

2- (6-Amino-pyridin-3-yl) -hexahydro-pyrido [l, 2-a] pyrazin-1-one (0.060 g, 0.244 mmol) was reacted with 2- Cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (0.072 g, 0.246 mmol, 1.01 eq) Pyrrolo [2,3-d] pyrimidine-6-carboxylate (prepared according to the method described in Example 1) Acid dimethylamide (0.070 g, 0.136 mmol) in 56% yield.

Example 100

Pyridin-2-ylamino] -7H-pyrrolo [2,3-a] pyrimidin- -d] pyrimidine-6-carboxylic acid dimethylamide.

2- (6-Amino-pyridin-3-yl) -hexahydro-pyrido [l, 2-a] pyrazin-1-one (0.060 g, 0.244 mmol) was reacted with 2- Cyclohexyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (0.075 g, 0.244 mmol, 1.0 eq) Pyrrolo [2,3-d] pyrimidine-6-carboxylate (prepared according to the method described in Example 1) Acid dimethylamide (0.020 g, 0.039 mmol) in 16% yield.

Example 101

N, N-dimethyl-2- (5 - ((1R, 3R, 5S) -2 '-oxo-8- azaspiro [bicyclo [3.2.1] octane- 3-yl) pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine- 6- carboxamide.

Step 1:

(6-nitropyridin-3-yl) -8-azaspiro [bicyclo [3.2.1] octane-3,5'-oxazolidin] -2'-one .

(1R, 3r, 5S) -8-azaspiro [bicyclo [3.2.1] octane-3,5'-oxazolidin] -2'-one (0.488 g, 1.728 3R, 5S) -3 ' -methyl-2, &lt; / RTI &gt; (6-nitropyridin-3-yl) -8- azaspiro [bicyclo [3.2.1] octane-3,5'-oxazolidine] -2'-one (0.615 g, 1.521 mmol) .

Step 2:

Aza-spiro [bicyclo [3.2.1] octane-3,5'-oxazolidine] -2'-one .

Nitro group reduction According to the procedure 1, (1R, 3R, 5S) -3 '-( 6-nitropyridin-3-yl) -8- azaspiro [bicyclo [3.2.1] 3-yl) -8-azaspiro [bicyclo [3.2.1] hept-2-ene (0.705 g, Oxo-3,5'-oxazolidin] -2'-one as an off-white solid (0.356 g, 0.951 mmol).

Step 3:

Pyrrolo [2,3-d] pyrimidin-2-ylamino (2-oxo-pyridin-2-yl) ) Pyridin-3-yl) -2'-oxo-8-azaspiro [bicyclo [3.2.1] octane-3,5'-oxazolidine] -8-carboxylate.

3-yl) -8-azaspiro [bicyclo [3.2.1] octane-3, 5 ' Oxazolidine] -2'-one with 2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide to give (lR, pyrrolo [2,3-d] pyrimidin-2-ylamino) pyridin-3-yl) - (6- (7-cyclopentyl-6- (dimethylcarbamoyl) Oxo-8-azaspiro [bicyclo [3.2.1] octane-3,5'-oxazolidine] -8-carboxylate as a dark solid (0.458 g, 0.726 mmol) And used in the subsequent step without purification.

Step 4:

N, N-dimethyl-2- (5 - ((1R, 3R, 5S) -2 '-oxo-8- azaspiro [bicyclo [3.2.1] octane- Pyridin-3-yl) pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

Deprotection According to Method 1, (lR, 3r, 5S) -tert-butyl 3 '-( 6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H- pyrrolo [ Yl) -2'-oxo-8-azaspiro [bicyclo [3.2.1] octane-3,5'-oxazolidine] -8-carboxylate 0.450 g, 0.713 mmol) was added to a solution of 7-cyclopentyl-N, N-dimethyl-2- (5 - ((1R, 3R, 5S) -2'-oxo-8- azaspiro [bicyclo [3.2.1] Pyrido [2,3-d] pyrimidine-6-carboxamide (0.286 g, 0.517 mmol) To 73% yield.

Example 102

3-ylmethyl-2'-oxo-8-azaspiro [bicyclo [3.2.1] octane-3, Pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

3-ylmethyl-2'-oxo-8-azaspiro [bicyclo [3.2.1] octane-3, Pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

According to General Reduction Alkylation Method 1, 7-cyclopentyl-N, N-dimethyl-2- (5 - ((1R, 3R, 5S) -2 ' -oxo- Pyrido [2,3-d] pyrimidine-6-carboxamide (0.216 g, 0.407 mmol, 8-aza spiro [bicyclo [3.2.1] octane-2-carbonyl] -2-oxo-8- Pyrido [2,3-d] pyrimidine-6-carboxamide as a white solid (0.120 g, 0.220 &lt; RTI ID = 0.0 & mmol) &lt; / RTI &gt; in 54% yield.

Example 103

N-dimethyl-2- (5- (2-oxo-1-oxa-3,8-diazaspiro [4.6] undecan-3- yl) pyridin- 7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

Step 1:

Preparation of 3- (6-Nitro-pyridin-3-yl) -2-oxo-1-oxa-3,8-diaza-spiro [4.6] undecane-8-carboxylic acid tert-

Spiro [4.6] undecane-8-carboxylic acid tert-butyl ester (0.510 g, 1.887 mmol) (reference: Bromo-2-nitropyridine (0.400 g, 1.971 mmol, 1.05 eq.) To give 3- (6-nitro-pyridin- -Oxo-1-oxa-3,8-diaza-spiro [4.6] undecane-8-carboxylic acid tert-butyl ester as a brown solid (0.684 g, 1.743 mmol) in 92% yield.

Step 2:

Preparation of 3- (6-Amino-pyridin-3-yl) -2-oxo-1-oxa-3,8-diaza-spiro [4.6] undecane-8-carboxylic acid tert-

Nitro-pyridine-3-yl) -1-oxa-3,8-diaza-spiro [4.6] undecan-2-one (0.620 g, 1.580 mmol) Spiro [4.6] undecane-8-carboxylic acid tert-butyl ester as an off-white solid ( 0.532 g, 1.47 mmol) in 93% yield.

Step 3:

N-dimethyl-2- (5- (2-oxo-1-oxa-3,8-diazaspiro [4.6] undecan-3- yl) pyridin- 7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

Spiro [4.6] undecan-2-one (0.100 g, 0.276 mmol) was reacted according to general NC coupling procedure 1 to give 3- (6-amino-pyridin- ) Was combined with 2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide (0.081 g, 0.276 mmol, 1.0 eq.) To give 7-cyclopentyl- Pyridin-2-ylamino) -7H-pyrrolo [2, 5-dihydro- , 3-d] pyrimidine-6-carboxamide as a white solid (0.075 g, 0.139 mmol) in 50% yield.

Example 104

Spiro [4.6] undec-3-yl) -pyridin-2-ylamino] - 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Step 1

(8-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.6] undecan-3- yl) pyridin- 2- Ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide

N-dimethyl-2- (5- (2-oxo-1-oxa-3,8-diazaspiro [4.6] undecan-3- yl) Pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide with 7- cyclopentyl-N, Pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carbox Amide (0.062 g, 0.112 mmol) in 77% yield.

Example 105

Spiro [4.6] undec-3-yl) -pyridin-2-ylamino] - (5-fluoro- 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Step 1:

(S) -3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2-ylamino) -pyridin- Spiro [4.6] undecane-8-carboxylic acid tert-butyl ester.

According to general NC coupling procedure 1, (S) -3- (6- amino-pyridin-3-yl) -2-oxo-1-oxa-3,8-diaza- spiro [4.6] undecane-8 -Carboxylic acid tert-butyl ester was combined with 2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine- 6- carboxylic acid dimethylamide to give (S) -3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3-d] pyrimidin-2- ylamino) -pyridin- Diaza-spiro [4.6] undecane-8-carboxylic acid tert-butyl ester as a white solid (0.075 g, 0.115 mmol) in 35% yield.

Step 2:

Spiro [4.6] undec-3-yl) -pyridin-2-ylamino] - (5-fluoro- 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Deprotection According to Method 1, (S) -3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- Spiro [4.6] undecane-8-carboxylic acid tert-butyl ester was reacted with 7-cyclopentyl-2- [5 - ( Pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidin- 6-carboxylic acid dimethylamide as a white solid (0.040 g, 0.076 mmol) in 67% yield.

Example 106

Spiro [4.6] undec-3-yl) -pyridin-2-ylamino] - 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Step 1

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridin-3-yl] -2,2,3,4-tetrahydroisoquinolin- -Oxa-1-oxa-3,8-diaza-spiro [4.6] undecane-8-carboxylic acid tert-butyl ester

Spiro [4.6] undecane-8 &lt; RTI ID = 0.0 &gt; -Carboxylic acid tert-butyl ester was coupled with 2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide to give (R) -3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3-d] pyrimidin-2- ylamino) -pyridin- Diaza-spiro [4.6] undecane-8-carboxylic acid tert-butyl ester as a white solid (0.175 g, 0.272 mmol) in 66% yield.

Step 2

Spiro [4.6] undec-3-yl) -pyridin-2-ylamino] - 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Deprotection Following method 1, the title compound was obtained from (R) -3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- Spiro [4.6] undecane-8-carboxylic acid tert-butyl ester was reacted with 7-cyclopentyl-2- [5 - ( Yl) -pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidin- 6-carboxylic acid dimethylamide as a white solid (0.090 g, 0.167 mmol) in 70% yield.

Example 107

Synthesis of 7-cyclopentyl-N, N-dimethyl-2- (5- (2-oxo-1-oxa-3,7-diazaspiro [4.5] decan- - pyrrolo [2,3-d] pyrimidine-6-carboxamide

Step 1:

Preparation of 3- (6-Nitro-pyridin-3-yl) -2-oxo-1-oxa-3,7-diaza-spiro [4.5] decane-7-carboxylic acid tert-

4-deaza-spiro [4.5] decane-7-carboxylic acid tert-butyl ester (0.546 g, 2.130 mmol) 2-nitropyridine (0.432 g, 2.130 mmol, 1.0 eq.) To give 3- (6-nitro-pyridin-3-yl) -2- Oxa-1-oxa-3,7-diaza-spiro [4.5] decane-7-carboxylic acid tert-butyl ester as a brown solid (0.709 g, 1.735 mmol) in 81% yield.

Step 2:

Preparation of 3- (6-Amino-pyridin-3-yl) -2-oxo-1-oxa-3,7-diaza-spiro [4.5] decane-7-carboxylic acid tert-

Nitrogen Reduction According to the procedure 1, 3- (6-nitro-pyridin-3-yl) -2-oxo-1-oxa-3,7- diaza- spiro [4.5] decane- Butyl ester (0.605 g, 1.599 mmol) was reacted with 3- (6-amino-pyridin-3-yl) -2-oxo-1-oxa-3,7-diaza- spiro [4.5] decane- tert-butyl ester (0.549 g, 1.45 mmol) in 92% yield.

Step 3:

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridin-3-yl] -2-oxo-1, -Oxa-3,7-diaza-spiro [4.5] decane-7-carboxylic acid tert-butyl ester

3-yl) -2-oxo-1-oxa-3,7-diaza-spiro [4.5] decane-7- carboxylic acid tert -Butyl ester was combined with 2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide (0.084 g, 0.287 mmol, 1.0 eq) Pyridin-2-ylamino) -pyridin-3-yl] -2-oxo-1-oxa-3,7-dihydro- , 7-diaza-spiro [4.5] decane-7-carboxylic acid tert-butyl ester, which was used directly in the following BOC deprotection.

Step 4

Synthesis of 7-cyclopentyl-N, N-dimethyl-2- (5- (2-oxo-1-oxa-3,7-diazaspiro [4.5] decan- - pyrrolo [2,3-d] pyrimidine-6-carboxamide

Deprotection According to Method 1, 3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2- ylamino) -pyridin- ] -2-oxo-1-oxa-3,7-diaza-spiro [4.5] decane-7- carboxylic acid tert- butyl ester was converted to 7-cyclopentyl- Pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carbox Amide to give a white solid (0.070 g, 0.135 mmol) in 47% yield.

Example 108

N, N-dimethyl-2- (5- (7-methyl-2-oxo-1-oxa-3,7-diazaspiro [4.5] decan- Amino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

According to General Reductive Alkylation Method 1, 7-cyclopentyl-N, N-dimethyl-2- (5- (2-oxo-1-oxa-3,7- diazaspiro [4.5] decan- Yl) amino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide (0.116 mmol) Pyrrolo [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-1-oxa-3,7-diazaspiro [4.5] decan- Carboxamide, which was isolated as an off-white solid (0.052 g, 0.098 mmol) in 85% yield.

Example 109

4-yl) -pyridin-2-ylamino] -7H (4S) -2-oxo-1-oxa- - pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Step 1:

(S) -3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2-ylamino) -pyridin- -Oxa-1-oxa-3,7-diaza-spiro [4.5] decane-7-carboxylic acid tert-butyl ester

4-diaza-spiro [4.5] decan-7-yl) -2-oxo-1-oxa- Carboxylic acid tert-butyl ester was combined with 2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine- 6- carboxylic acid dimethylamide to give (S) -3- [6- 2,3-d] pyrimidin-2-ylamino) -pyridin-3-yl] -2-oxo-1-oxa-3,7-dihydro-pyrazolo [ -Diaza-spiro [4.5] decane-7-carboxylic acid tert-butyl ester as a white solid (0.115 g, 0.190 mmol) in 43% yield.

Step 2:

4-yl) -pyridin-2-ylamino] -7H (4S) -2-oxo-1-oxa- - pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Deprotection According to Method 1, (S) -3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- Spiro [4.5] decane-7-carboxylic acid tert-butyl ester was reacted with 7-cyclopentyl-2- [5 - ((S Pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidin- 6-carboxylic acid dimethylamide (0.062 g, 0.123 mmol) in 71% yield.

Example 110

7-diaza-spiro [4.5] dec-3-yl) -pyridin-2- ylamino] -7H - pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Step 1

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridin-3-yl] -2,2,3,4-tetrahydroisoquinolin- -Oxa-1-oxa-3,7-diaza-spiro [4.5] decane-7-carboxylic acid tert-butyl ester

4-diaza-spiro [4.5] decan-7-yl) -2-oxo-1-oxa- Carboxylic acid tert-butyl ester was coupled with 2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide to give (R) -3- [6- 2,3-d] pyrimidin-2-ylamino) -pyridin-3-yl] -2-oxo-1-oxa-3,7-dihydro-pyrazolo [ -Diaza-spiro [4.5] decane-7-carboxylic acid tert-butyl ester as a white solid (0.175 g, 0.275 mmol) in 64% yield.

Step 2

7-diaza-spiro [4.5] dec-3-yl) -pyridin-2- ylamino] -7H - pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Deprotection Following method 1, the title compound was obtained from (R) -3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- Spiro [4.5] decane-7-carboxylic acid tert-butyl ester was reacted with 7-cyclopentyl-2- [5 - ((R Pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidin- Carboxylic acid dimethylamide as a white solid (0.120 g, 0.238 mmol) in 85% yield.

Example 111

Pyridin-2-ylamino] -7H-pyrrolo [2,3-d] quinolin-2- ] Pyrimidine-6-carboxylic acid dimethylamide.

Step 1:

Preparation of 5- (6-nitro-pyridin-3-yl) -2,5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester.

(4.75 g, 23.4 mmol, 1.0 eq.) And (R, R) -2,5-diaza-bicyclo [2.2.1] heptane-2- carboxylic acid tert- butyl The ester (5.04 g, 25.4 mmol, 1.1 eq.) Was combined in DMF (60 mL) and heated to 100 &lt; 0 &gt; C. Cool the reaction, dilute with ethyl acetate, and wash several times with water, then brine, and the organic layer dried (Na ₂ SO _4), filtered and concentrated the organic portion. The crude material was purified by chromatography eluting with a MeOH / DCM mixture to give the desired product (4.3 g, 57%).

Step 2:

2,5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester

Carboxylic acid tert-butyl ester (1.00 g, 3.12 mmol, 1.0 eq) was added to a solution of 5- (6-nitro-pyridin- Was hydrogenated in a Parr flask at 50 psi with Pd / C (0.250 g) in ethyl acetate (25 mL) for 16 hours. The reaction contents were filtered through celite, washed with MeOH, and the filtrate was concentrated. The crude material was purified by chromatography using a (MeOH / CH ₂ Cl ₂ ) mixture to give a purple solid (0.648 g, 68%).

Step 3:

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridin-3-yl] -piperazin-l- Preparation of carboxylic acid tert-butyl ester

7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide (200 mg, 0.683 mmol, 1.0 eq.) Was reacted using general Buchwald method 1 2.2.1] heptane-2-carboxylic acid tert-butyl ester (218 mg, 0.751 mmol, 1.1 eq.) And 5- (6-amino-pyridin- Pyrrolidin-2-ylamino) -pyridin-3-yl] -piperazin-1-one To a solution of 4- [6- (7-cyclopentyl-6-dimethylcarbamoyl- -Carboxylic acid tert-butyl ester (350 mg, 94% yield).

Step 4:

Pyridin-2-ylamino] -7H-pyrrolo [2,3-d] quinolin-2- ] Pyrimidine-6-carboxylic acid dimethylamide

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridin-3-yl] -piperazin-l- Carboxylic acid tert-butyl ester was treated with TFA using general deprotection method 2 for the removal of the BOC group to give 7-cyclopentyl-2- [5- (2,5-diaza- bicyclo [2.2.1 ] Hept-2-yl) -pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide (117 mg, 47%).

Example 112

Pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidin- ] Pyrimidine-6-carboxylic acid dimethylamide.

Step 1:

Preparation of 3- (6-nitro-pyridin-3-yl) -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

(200 mg, 0.985 mmol, 1.0 eq.) And (3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert (6-nitro-pyridin-3-yl) -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylate Acid tert-butyl ester (242 mg, 74%) was obtained.

Step 2:

Preparation of 3- (6-amino-pyridin-3-yl) -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

According to Example 78 step 2, 5- (6-nitro-pyridin-3-yl) -2,5-diaza-bicyclo [2.2.1] heptane- 2- carboxylic acid tert- (6-amino-pyridin-3-yl) -3,8-diaza-bicyclo [3.2.1] octane-8-carbaldehyde Butyl ester tert-butyl ester (205 mg, 94%).

Step 3:

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridin-3-yl] -3,8-diazolo [3,4-d] pyrimidin- Apos; -bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (139 mg, 0.476 mmol, 1.0 eq.), Using general Buchwald method 1, Carboxylic acid tert-butyl ester (145 mg, 0.476 mmol, 1.0 eq.) And 3- (6-amino-pyridin- Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridin-3-yl] -3,8-dihydro- Diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (143 mg, 51% yield).

Step 4:

Pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidin- ] Pyrimidine-6-carboxylic acid dimethylamide

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridin-3-yl] -3,8-diazolo [3,4-d] pyrimidin- Butylcyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester was treated with TFA using general deprotection method 2 for the removal of the BOC group to give 7-cyclopentyl-2- [5- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide as a light yellow solid, MS: m / e = (83 mg, 76%).

Example 113 Synthesis of

Step 1

Oxo-1,7-diaza-spiro [4.4] nonane-1-carboxylic acid tert-butyl ester 1

To a solution of 1,7-diazaspiro [4.4] nonan-6-one hydrochloride (0.98 g, 5.4 mmol) in dichloromethane tert-butyl dicarbonate (1.41 g, 6.48 mmol) and triethylamine , 13.5 mmol). The resulting solution was stirred overnight at room temperature. The solution was diluted with water and extracted with dichloromethane. The organic phase was separated, dried, filtered and concentrated to give the product, 6-oxo-1,7-diaza-spiro [4.4] nonane-1 -carboxylic acid tert- butyl ester as a white powder (1.3 g) % Yield, which was used directly without further purification.

Step 2

Preparation of 7- (6-nitro-pyridin-3-yl) -6-oxo-1,7-diaza-spiro [4.4] nonane-1-carboxylic acid tert-butyl ester

Spiro [4.4] nonane-1-carboxylic acid tert-butyl ester (1.3 g, 5.41 mmol) was reacted with 5-bromo-2- (1.10 g, 5.41 mmol) was coupled to 7- (6-nitro-pyridin-3-yl) -6-oxo-1,7-diaza- spiro [4.4] nonane-1 -carboxylic acid tert- butyl Ester (1.55 g) was obtained in 79% yield.

Step 2

Preparation of 7- (6-amino-pyridin-3-yl) -6-oxo-1,7-diaza-spiro [4.4] nonane-1-carboxylic acid tert-butyl ester

Nitro group Reduction According to procedure 1, (7- (6-nitro-pyridin-3-yl) -6-oxo-1,7-diaza- spiro [4.4] nonane-1 -carboxylic acid tert- 1.55 g, 4.28 mmol) was added to a solution of 7- (6-amino-pyridin-3-yl) -6-oxo-1,7-diaza- spiro [4.4] nonane- 1 -carboxylic acid tert- ) To 70% yield.

Step 3

7- (6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3-d] pyrimidin- , 7-diaza-spiro [4.4] nonane-1-carboxylic acid tert-butyl ester.

7-diaza-spiro [4.4] nonane-1-carboxylic acid tert-butyl ester (prepared according to general NC coupling procedure 1 7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.34 mmol) was combined and purified by silica gel column chromatography 6-Dimethylcarbamoyl-7H-pyrrolo [2,3-d] pyrimidin-2-yl-amino- Oxo-1,7-diaza-spiro [4.4] nonane-1-carboxylic acid tert-butyl ester (100 mg) in 49% yield.

Step 4

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- d] pyrimidine-6-carboxylic acid dimethylamide

Deprotection According to Method 1, 7- (6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- (100 mg, 0.17 mmol) was reacted with 7-cyclopentyl-2- [5- (6-oxo-thiophene- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (80 &lt; RTI ID = 0.0 & mg) in 96% yield.

Example 114

Step 1

Preparation of 2- (6-nitro-pyridin-3-yl) -1-oxo-2,9-diaza-spiro [5,5] undecane-9-carboxylic acid tert-butyl ester

Spiro [5,5] undecane-9-carboxylic acid tert-butyl ester (200 mg, 0.74 mmol) in dioxane was added to a solution of 5 -Bromo-2-nitropyridine (150 mg, 0.74 mmol) to obtain 2- (6-nitro-pyridin- ] Undecane-9-carboxylic acid tert-butyl ester (100 mg) in 34% yield.

Step 2

Preparation of 2- (6-amino-pyridin-3-yl) -1-oxo-2,9-diaza-spiro [5,5] undecane-9-carboxylic acid tert-butyl ester

Nitro group Reduction According to procedure 1, the title compound was obtained from 2- (6-nitro-pyridin-3-yl) -1-oxo-2,9-diaza- spiro [5,5] undecane-9- (100 mg, 0.26 mmol) was reacted with 2- (6-amino-pyridin-3-yl) -1-oxo-2,9-diaza- spiro [5,5] undecane-9- Butyl ester (92 mg) in 100% yield.

Step 3

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridin-3-yl] -1-oxo-2, 9-diaza-spiro [5,5] undecane-9-carboxylic acid tert-butyl ester

Spiro [5,5] undecane-9-carboxylic acid tert-butyl ester was prepared according to general NC coupling procedure 1 from 2- (6-amino-pyridin- Butyl ester (98 mg, 0.27 mmol) was combined with 2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid dimethylamide (80 mg, 0.27 mmol) Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridin-3-yl] -1-oxo-2, -Diaza-spiro [5,5] undecane-9-carboxylic acid tert-butyl ester (155 mg) in 92% yield.

Step 4

Pyridin-2-ylamino] -7H-pyrrolo [2, &lt; RTI ID = 0.0 &gt; 3-d] pyrimidine-6-carboxylic acid dimethylamide

Deprotection According to Method 1, 2 [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2- ylamino) -pyridin- Spiro [5,5] undecane-9-carboxylic acid tert-butyl ester (45 mg, 0.07 mmol) was reacted with 7-cyclopentyl-2- [5- Pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid Dimethylamide (30 mg) in 80% yield.

Example 115

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- d] pyrimidine-6-carboxylic acid dimethylamide

Step 1

Preparation of 2- (6-nitro-pyridin-3-yl) -hexahydro-pyrrolo [1,2-a] pyrazin-

According to general NC coupling procedure 1, hexahydro-pyrrolo [1,2-a] pyrazin-1-one was combined with 5-bromo-2-nitropyridine to give 2- (6-nitro- ) -Hexahydro-pyrrolo [1,2-a] pyrazin-1-one (250 mg) in 66% yield.

Step 2

Preparation of 2- (6-amino-pyridin-3-yl) -hexahydro-pyrrolo [1,2-a] pyrazin-1-one.

Nitro-pyrrolo [1,2-a] pyrazin-1-one was reacted with 2- (6-amino-pyridin- -Yl) -hexahydro-pyrrolo [1,2-a] pyrazin-1-one (220 mg) in 99% yield.

Step 3

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- d] pyrimidine-6-carboxylic acid dimethylamide.

According to general NC coupling procedure 1 2- (6-Amino-pyridin-3-yl) -hexahydro-pyrrolo [1,2- a] pyrazin- 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide in accordance with the general method of example 1, step 7c to yield 7-cyclopentyl-2- [5- (1- oxo-hexahydro- Pyridin-6-carboxylic acid dimethylamide (67 mg) was obtained in 31% yield.

Example 116

2-ylamino) -N, N-dimethyl-7H-pyrrolo [2,3-c] pyridin- 2,3-d] pyrimidine-6-carboxamide

Step 1

Preparation of 2- (6-nitro-pyridin-3-yl) -octahydro-pyrrolo [1,2-a] pyrazine

2-Nitropyridine (483 mg, 2.38 mmol) was combined with octahydropyrrolo [l, 2-c] pyrimidine (300 mg, 2.38 mmol) according to general NC coupling procedure 1 to give 2- (6-nitro-pyridin-3-yl) -octahydro-pyrrolo [1,2-a] pyrazine (270 mg) in 45% yield.

Step 2

Preparation of 5- (hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl) pyridin-

Pyrido [1,2-a] pyrazine (270 mg, 1.09 mmol) was reacted with 5- (hexahydropyrrolo [ [L, 2-a] pyrazin-2 (lH) -yl) pyridine-2-amine (223 mg) in 94% yield.

Step 3

2-ylamino) -N, N-dimethyl-7H-pyrrolo [2,3-c] pyridin- 2,3-d] pyrimidine-6-carboxamide

2,3-d] pyrimidine-6-carboxamide (100 mg, 0.34 mmol) was reacted with 2-chloro-7-cyclopentyl- (74.6 mg, 0.34 mmol) was combined with 5- (hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl) pyridin- Yl) pyridin-2-ylamino) -N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6-carbaldehyde (60 mg) in 37% yield.

Example 117

2-ylamino) -7H-pyrrolo [2,3-d] pyrimidin-2- 2,3-d] pyrimidine-6-carboxamide

Step 1

Preparation of tert-butyl 2- (6-aminopyridin-3-yl) -3-oxo-2,8-diazaspiro [4.5] decane-8-

Nitro group Reduction According to the procedure 1, tert-butyl 2- (6-nitropyridin-3-yl) -3-oxo-2,8-diazaspiro [4.5] decane-8- mmol) was converted to 67% yield with tert-butyl 2- (6-aminopyridin-3-yl) -3-oxo-2,8-diazaspiro [4.5] decane-8- .

Step 2

Pyrrolo [2,3-d] pyrimidin-2-ylamino) pyridin-3-yl) -1-oxo-pyrrolidine- Preparation of 2,8-diazaspiro [4.5] decane-8-carboxylate.

7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide (135 mg, 0.46 mmol) Was combined with tert-butyl 2- (6-aminopyridin-3-yl) -3-oxo-2,8-diazaspiro [4.5] decane-8- carboxylate (160 mg, 0.46 mmol) Pyrrolo [2,3-d] pyrimidin-2-ylamino) pyridin-3-yl) -1-oxo-pyrrolidine- 2,8-diazaspiro [4.5] decane-8-carboxylate (270 mg) was obtained in 97% yield.

Step 3

2-ylamino) -7H-pyrrolo [2,3-d] pyrimidin-2- 2,3-d] pyrimidine-6-carboxamide.

According to the deprotection method 1, tert-butyl 2- (6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3- d] pyrimidin- Diazaspiro [4.5] decane-8-carboxylate (270 mg, 0.45 mmol) was reacted with 7-cyclopentyl-N, N-dimethyl- Pyrrolo [2,3-d] pyrimidine-6-carboxamide (prepared according to the method described in Example 1) 86 mg) in 38% yield.

Example 118

Cyclopentyl-N, N-dimethyl-2- (5- (5'-oxo-8-azaspiro [bicyclo [3.2.1] octane-3,3'-pyrrolidin] ) Pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide

Step 1

aza-spiro [bicyclo [3.2.1] octane-3,3'-pyrrolidine] -8-carboxylate &Lt; / RTI &gt;

Nitro group reduction According to the procedure 1, tert-butyl 1 '-( 6-nitropyridin-3-yl) -5'-oxo-8- azaspiro [bicyclo [3.2.1] (400 mg, 0.99 mmol) was reacted with tert-butyl 1 '- (6-aminopyridin-3-yl) -5'-oxo-8- azaspiro [bicyclo [3.2.1 ] Octane-3,3'-pyrrolidine] -8-carboxylate (150 mg) in 40% yield.

Step 2

pyrrolo [2,3-d] pyrimidin-2-ylamino) pyridin-3-yl) - (6- (7-cyclopentyl-6- (dimethylcarbamoyl) Preparation of 5'-oxo-8-azaspiro [bicyclo [3.2.1] octane-3,3'-pyrrolidine] -8-carboxylate.

7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide (162 mg, 0.55 mmol) Azepiro [bicyclo [3.2.1] octane-3,3'-pyrrolidine] -8-carbaldehyde was prepared from tert- butyl 1 '- (6-aminopyridin- (150 mg, 0.55 mmol) to give tert-butyl 1 '- (6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3- d] pyrimidin- -Amino) pyridin-3-yl) -5'-oxo-8-azaspiro [bicyclo [3.2.1] octane-3,3'- pyrrolidine] -8- 86% yield.

Step 3

Cyclopentyl-N, N-dimethyl-2- (5- (5'-oxo-8-azaspiro [bicyclo [3.2.1] octane-3,3'-pyrrolidin] ) Pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide.

According to general amide formation method 1, tert-butyl 1 '- (6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3- d] pyrimidin- Yl) -5'-oxo-8-azaspiro [bicyclo [3.2.1] octane-3,3'-pyrrolidine] -8-carboxylate (250 mg, 0.47 mmol) Cyclopentyl-N, N-dimethyl-2- (5- (5'-oxo-8-azaspiro [bicyclo [3.2.1] octane-3,3'-pyrrolidin] ) Pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide (56 mg) in 22% yield.

Example 119

Synthesis of 7-cyclopentyl-N, N-dimethyl-2- (5- (2-oxo-1-oxa-3,8-diazaspiro [4.5] decan- - pyrrolo [2,3-d] pyrimidine-6-carboxamide

Step 1

Preparation of tert-butyl 3- (6-nitropyridin-3-yl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate ester.

5-Bromo-2-nitropyridine (238 mg, 1.17 mmol) was reacted with tert-butyl 2-oxo-1-oxa-3,8-diazaspiro [4.5] decane- -Carboxylate (300 mg, 1.17 mmol) to give tert-butyl 3- (6-nitropyridin-3-yl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane- -Carboxylate ester (400 mg) in 90% yield.

Step 2

Preparation of tert-butyl 3- (6-aminopyridin-3-yl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate.

Nitrogen Reduction According to the procedure 1, tert-butyl 3- (6-nitropyridin-3-yl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8- (400 mg, 1.06 mmol) was reacted with tert-butyl 3- (6-aminopyridin-3-yl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8- 370 mg) in 100% yield.

Step 3

pyrrolo [2,3-d] pyrimidin-2-ylamino) pyridin-3-yl) -2,2-dimethyl- Oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate.

7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide (133 mg, 0.45 mmol) Was combined with tert-butyl 3- (6-aminopyridin-3-yl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8- pyrrolo [2,3-d] pyrimidin-2-ylamino) pyridin-3-yl) -2,2-dimethyl- Oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate (170 mg) in 62% yield.

Step 4

Synthesis of 7-cyclopentyl-N, N-dimethyl-2- (5- (2-oxo-1-oxa-3,8-diazaspiro [4.5] decan- -Pyrrolo [2,3-d] pyrimidine-6-carboxamide.

Deprotection According to Method 1, tert-butyl 3- (6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3- d] pyrimidin- Diazaspiro [4.5] decane-8-carboxylate (150 mg, 0.25 mmol) was reacted with 7-cyclopentyl-N, N-dimethyl- Pyridin-3-yl) pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidin- 6-carboxamide (170 mg) in 62% yield.

Example 120

N, N'-dimethyl-2- (5- (5'-oxo-8-azaspiro [bicyclo [3.2.1] octane-3,3'- pyrrolidin] Ylamino) -7- (tetrahydro-2H-pyran-3-yl) -7H-pyrrolo [2,3- d] pyrimidine- 6- carboxamide

Step 1

pyrrolo [2,3-d] pyrimidin-2-ylmethyl) -2,3-dimethyl-l- (6- (6- (dimethylcarbamoyl) -7- (tetrahydro- Ylamino) pyridin-3-yl) -5'-oxo-8-azaspiro [bicyclo [3.2.1] octane-3,3'-pyrrolidine] -8-carboxylate.

Pyrrolidin-2-yl] pyrimidin-6-yloxy) -acetic acid ethyl ester was prepared according to general NC coupling procedure 1 from 2-chloro-N, N-dimethyl-7- (tetrahydro- Carboxamide (70.6 mg, 0.23 mmol) was reacted with tert-butyl 1 '-( 6-aminopyridin-3-yl) -5 ' -oxo-8- azaspiro [bicyclo [3.2.1] - (6- (dimethylcarbamoyl) -7- (tetrahydro-2H-pyran-2-yl) -pyrrolidine] -8- carboxylate (62 mg, 0.23 mmol) Yl) -5'-oxo-8-azaspiro [bicyclo [3.2.1] octane- 3,3'-pyrrolidine] -8-carboxylate (71 mg) in 57% yield.

Step 2

N, N'-dimethyl-2- (5- (5'-oxo-8-azaspiro [bicyclo [3.2.1] octane-3,3'- pyrrolidin] Ylamino) -7- (tetrahydro-2H-pyran-3-yl) -7H-pyrrolo [2,3-d] pyrimidine- 6- carboxamide.

Deprotection According to Method 1, tert-butyl 1 '- (6- (6- (dimethylcarbamoyl) -7- (tetrahydro- 2H- pyran- d] pyrimidin-2-ylamino) pyridin-3-yl) -5'-oxo-8-azaspiro [bicyclo [3.2.1] octane-3,3'-pyrrolidine] (68 mg, 0.125 mmol) was dissolved in N, N-dimethyl-2- (5- (5'-oxo-8-aza spiro [bicyclo [3.2.1] octane-3,3'-pyrrolidine] Pyridin-2-ylamino) -7- (tetrahydro-2H-pyran-3-yl) -7H- pyrrolo [2,3- d] pyrimidine-6- carboxamide (17 mg ) In 25% yield.

Example 121

Pyridin-2-ylamino) -7- (tetrahydro-2H-pyran-4-yl) 3-yl) -7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide

Step 1

pyrrolo [2,3-d] pyrimidin-2-yl (4-fluorobenzyl) Amino) pyridin-3-yl) -6-oxo-1,7-diazaspiro [4.4] nonane-1-carboxylate.

Pyrrolidin-2-yl] pyrimidin-6-yloxy) -acetic acid ethyl ester was prepared according to general NC coupling procedure 1 from 2-chloro-N, N-dimethyl-7- (tetrahydro- (76 mg, 0.246 mmol) was reacted with tert-butyl 7- (6-aminopyridin-3-yl) -6-oxo-1,7-diazaspiro [4.4] nonane- 1 -carboxylate mg, 0.246 mmol) was combined with tert-butyl 7- (6- (dimethylcarbamoyl) -7- (tetrahydro-2H-pyran- ] Pyrimidin-2-ylamino) pyridin-3-yl) -6-oxo-1,7-diazaspiro [4.4] nonane- 1 -carboxylate (107 mg) in 72% yield.

Step 2

Pyridin-2-ylamino) -7- (tetrahydro-2H-pyran-4-yl) 3-yl) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide.

Deprotection According to Method 1, tert-butyl 7- (6- (6- (dimethylcarbamoyl) -7- (tetrahydro-2H-pyran-3- yl) -7H- pyrrolo [2,3- d Pyridin-3-yl) -6-oxo-1,7-diazaspiro [4.4] nonane-1-carboxylate (100 mg, 0.165 mmol) was dissolved in N, Pyridin-2-ylamino) -7- (tetrahydro-2H-pyran-3-yl) - Was converted to 74% yield with 7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide (62 mg).

Example 122

Synthesis of 7-cyclopentyl-2- [5- (4-oxo-3,9-diaza-bicyclo [4.2.1] non-3-yl) -pyridin- 2-ylamino] -7H- pyrrolo [ , 3-d] pyrimidine-6-carboxylic acid dimethylamide.

Step 1

Preparation of 4-oxo-3,9-diaza-bicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester.

10.53 grams (45.7 mmol) of racemic 9-benzyl-3,9-diaza-bicyclo [4.2.1] nonan-4-one, 100 ml of methanol and 20 ml of tetrahydrofuran were added to a 500 ml Parr shaker bottle Respectively. At one time, 11 g (50.4 mmol) of di-tert-butyl di-carbonate were added. The mixture was then placed under nitrogen and about 0.5 grams of 10% palladium on carbon was added. The resulting mixture was hydrogenated at about 50 psi hydrogen with shaking for 36 h. The mixture was removed from the Parr shaker and about 100 ml of dichloromethane and 25 grams of celite were added and stirred. The mixture was filtered through a pad of celite. The pad was washed with an excess of dichloromethane. The organics were combined and concentrated to a thick residue which was coagulated under vacuum. The solid was recrystallized from dichloromethane / heptane and the white solid was dried under vacuum to yield 10.63 grams of 4-oxo-3,9-diaza-bicyclo [4.2.1] nonane-9-carboxylic acid tert- 98% yield.

Step 2

Preparation of 3- (6-nitro-pyridin-3-yl) -4-oxo-3,9-diazabicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester.

Following the general NC coupling procedure 1, 1.86 g (7.72 mmol) of 4-oxo-3,9-diaza-bicyclo [4.2.1] nonane-9-carboxylic acid tert- (6-nitro-pyridin-3-yl) -4-oxo-3, 9-diazabicyclo [3.2.1] heptane was obtained by recrystallization from CH ₂ Cl ₂ - Cyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester (1.59 g) in 58% yield. TLC Rf about 0.45 (75% ethyl acetate-heptane)

Step 3

Preparation of 3- (6-amino-pyridin-3-yl) -4-oxo-3,9-diaza-bicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester.

Nitrogen Reduction According to the procedure 1, 3- (6-nitro-pyridin-3-yl) -4-oxo-3,9-diazabicyclo [4.2.1] nonane-9-carboxylic acid tert- 1.59 grams (4.24 mmol) of 3- (6-amino-pyridin-3-yl) -4-oxo-3,9-diaza- bicyclo [4.2.1] nonane-9- carboxylic acid tert- butyl ester (1.41 grams) in 98% yield.

Step 4

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridin-3-yl] -4-oxo-3,7- , 9-diaza-bicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester.

Diaza-bicyclo [4.2.1] nonane-9-carboxylic acid tert (tert-butoxycarbonylamino) -butyl ester of 2-chloro-7-cyclopentyl--N, N- dimethyl -7H- pyrrolo [2,3-d] pyrimidine-6-carboxylic SiO ₂ gel were combined and the carboxamide chromatography (5-8% CH ₃ OH- ethyl acetate), and then 3- [6- (7-cyclopentyl-6-dimethylcarbamoyl -7H- pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridin -3 0.57 grams (95% yield) of TLC RF was obtained in a yield of 5% CH &lt; RTI ID = 0.0 &gt; ₃ &lt; / RTI &gt; OH-ethyl acetate.

Step 5

Synthesis of 7-cyclopentyl-2- [5- (4-oxo-3,9-diaza-bicyclo [4.2.1] non-3-yl) -pyridin- 2-ylamino] -7H- pyrrolo [ , 3-d] pyrimidine-6-carboxylic acid dimethylamide di-hydrochloride salt.

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridin-3-yl] -4-oxo-3,7- , 9-diaza-bicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester (0.55 grams, 0.96 mmol) was added 15 ml ethyl acetate. The mixture was stirred at room temperature under N ₂ and cooled to ice bath temperature. To this mixture was added 5 ml of 4N HCl in dioxane. The resulting mixture was allowed to stir until all the starting material was consumed. The resulting mixture was stirred by HPLC-MS until all starting material was consumed. To the mixture was added 50 ml of a 1: 1 mixture of ethyl acetate / diethyl ether to precipitate solids. The solid was filtered and washed with a 1: 1 mixture of excess ethyl acetate / diethyl ether and dried to constant weight under vacuum to give 7-cyclopentyl-2- [5- (4-oxo- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide as a light brown solid; , 0.213 grams (45% yield).

Example 123

Synthesis of 7-cyclopentyl-2- [5- ((lR, 6S) -4-oxo-3,9-diaza-bicyclo [4.2.1] 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Yl) -pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidin- [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (235 mg) was separated by chiral separation to give approximately the same amount of (+) and (-) enantiomers.

Synthesis of 7-cyclopentyl-2- [5- ((lR, 6S) -4-oxo-3,9-diaza-bicyclo [4.2.1] 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Example 123

Synthesis of 7-cyclopentyl-2- [5- ((lR, 6S) -4-oxo-3,9-diaza-bicyclo [4.2.1] 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Step 1

Preparation of 3- (6-nitro-pyridin-3-yl) -4-oxo-3,9-diaza- bicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester.

5-Bromo-2-nitropyridine (1 g, 4.93 mmol) was reacted with tert-butyl 4-oxo-3,9-diazabicyclo [4.2.1] (1.18 gm, 4.93 mmol) was combined with tert-butyl 3- (6-nitropyridin-3-yl) -4-oxo-3,9-diazabicyclo [4.2.1] nonane-9- carboxylate (1.4 g) in 78% yield.

Step 2

1 g of racemic 3- (6-nitro-pyridin-3-yl) -4-oxo-3,9-diaza-bicyclo [4.2.1] nonane-9-carboxylic acid tert- conditions: the separation using 30% MeOH / 70 using a mobile phase of% CO ₂ 20x250 mm 5 um column for purification IA to (1S, 6R) -tert- butyl 3- (6-nitropyridin-3-yl) - Oxo-3,9-diazabicyclo [4.2.1] nonane-9-carboxylate.

3-yl) -4-oxo-3, 9-diazabicyclo [4.2.1] nonane-9-carboxylate and (1R, 6S) -tert- (1S, 6R) -tert-butyl 3- (6-nitropyridin-3-yl) -4-oxo-3,9-diazabicyclo [4.2.1] nonane-9-carboxylate (320 mg).

Step 3

Preparation of (1R, 6S) -3- (6-amino-pyridin-3-yl) -4-oxo-3,9-diazabicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester.

Nitro group Reduction According to the procedure 1, (1R, 6S) -tert-butyl 3- (6-nitropyridin-3-yl) -4-oxo-3,9-diazabicyclo [4.2.1] non- Carboxylate (360 mg, 0.96 mmol) was added to a solution of (lR, 6S) -3- (6- amino-pyridin- -9-carboxylic acid tert-butyl ester (293 mg) in 92% yield.

Step 4

Pyrrolo [2,3-d] pyrimidin-2-ylamino) pyridine-dicarboxylic acid dihydrochloride was obtained in the same manner as in (1R, 6S) 3-yl) -4-oxo-3,9-diazabicyclo [4.2.1] nonane-9-carboxylate.

According to general NC coupling procedure 1, (lR, 6S) -3- (6-amino-pyridin-3- yl) -4-oxo-3,9- diaza- bicyclo [4.2.1] -Carboxylic acid tert-butyl ester (0.548 g, 1.65 mmol) was reacted with 2-chloro-7-cyclopentyl-N, N-dimethyl-7H- pyrrolo [2,3- d] pyrimidine- (483 mg, 1.65 mmol) was combined with (lR, 6S) -tert-butyl 3- (6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H- pyrrolo [2,3- Yl) amino) pyridin-3-yl) -4-oxo-3,9-diazabicyclo [4.2.1] nonane-9-carboxylate (858 mg) in 88% yield.

Step 5

Synthesis of 7-cyclopentyl-2- [5- ((lR, 6S) -4-oxo-3,9-diaza-bicyclo [4.2.1] 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Deprotection According to Method 1, (lR, 6S) -tert-butyl 3- (6- (7-cyclopentyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3- d] pyrimidin- Yl) -4-oxo-3,9-diazabicyclo [4.2.1] nonane-9-carboxylate (858 mg, 1.46 mmol) was added to a solution of 7-cyclopentyl- Pyridin-2-ylamino] -7H-pyrrolo [2, &lt; / RTI &gt; 3-d] pyrimidine-6-carboxylic acid dimethylamide (700 mg) in 98% yield.

Example 124

Synthesis of 7-cyclopentyl-2- [5 - ((lS, 6R) -4-oxo-3,9-diaza-bicyclo [ 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide was prepared from the chiral separation of the racemate from that carried out prior to Example 122.

Example 125

Synthesis of 7-cyclopentyl-2- [5 - ((1R, 6S) -9-methyl-4-oxo- Ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid methylamide

Step 1

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridin-3-yl] -pyridin- -4-oxo-3,9-diaza-bicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester.

7-cyclopentyl-N-methyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide was reacted with (lR, 6S) -tert- (1R, 6S) -3- [6- (4-fluorophenyl) -5-methyl- (7-cyclopentyl-6-methylcarbamoyl-7H-pyrrolo [2,3-d] pyrimidin-2- ylamino) -pyridin- -Bicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester (200 mg) in 78% yield.

Step 2

Synthesis of 7-cyclopentyl-2- [5- ((lR, 6S) -4-oxo-3,9-diaza-bicyclo [4.2.1] 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid methylamide.

Deprotection According to Method 1, (lR, 6S) -3- [6- (7-cyclopentyl-6-methylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- Yl] -4-oxo-3,9-diaza-bicyclo [4.2.1] nonane-9-carboxylic acid tert- butyl ester was reacted with 7-cyclopentyl-2- [5- Pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidin- 6-carboxylic acid methylamide (550 mg) in 52% yield.

Step 3

Synthesis of 7-cyclopentyl-2- [5 - ((1R, 6S) -9-methyl-4-oxo- Ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid methylamide.

Synthesis of 7-cyclopentyl-2- [5 - ((1R, 6S) -4-oxo-3,9- diaza- bicyclo [4.2.1] non- Cyclopentyl-2- [5 - ((1R, 6S) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid methylamide was combined with formaldehyde to give 7- Pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidin- Methyl-6-carboxylic acid methylamide (100 mg) in 98% yield.

Example 126

Pyridazin-3-ylamino] -7H-pyrrolo [2,3-d] pyrimidin- d] pyrimidine-6-carboxylic acid dimethylamide

Step 1

Preparation of 3- (6-amino-pyridazin-3-yl) -3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester.

6-Chloro-pyridazin-3-ylamine (100 mg, 0.772 mmol) and 3,8-diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert- butyl ester 180 mg, 0.849 mmol) were pulverized together, placed in a sealed tube and heated to 130 [deg.] C for 16 hours. The reaction was allowed to cool to room temperature and the contents were then dissolved in a minimum amount of dichloromethane. The crude product was purified by silica gel chromatography using a 0-50% ethyl acetate heptane gradient to give 3- (6-amino-pyridazin-3-yl) -3,8-diaza- bicyclo [3.2.1 ] Octane-8-carboxylic acid tert-butyl ester (70.7 mg, 0.232 mmol) in 30% yield.

Step 2

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridazin-3-yl] -3,8-dihydro- Diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester.

7-cyclohexyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (25.2 mg, 0.082 mmol) was reacted with 3- 3-yl) -3,8-diaza-bicyclo [3.2.1] obtained in Example 1 was combined with silica gel purification (0-10% methanolic ethyl acetate gradient) to give 3- [6- Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridazin-3-yl] -3,8-diaza- bicyclo [3.2 1] octane-8-carboxylic acid tert-butyl ester (25 mg, 0.043 mmol).

Step 3

Pyridazin-3-ylamino] -7H-pyrrolo [2,3-d] pyrimidin- d] pyrimidine-6-carboxylic acid dimethylamide.

Deprotection According to Method 2, 3- [6- (7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- Tert-butyl ester (25 mg, 0.043 mmol) was reacted with 7-cyclohexyl-2- [6- (3, 8 Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (18 &lt; RTI ID = 0.0 & 0.0 &gt; mg, &lt; / RTI &gt; 0.038 mmol).

Example 127

N, N-dimethyl-2- (5- (4-oxo-3,9-diazabicyclo [4.2.1] Yl) pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide

Step 1

yl) phenyl) -6- (dimethylcarbamoyl) -7H-pyrrolo [2,3-d] pyrimidine Ylamino) pyridin-3-yl) -4-oxo-3,9-diazabicyclo [4.2.1] nonane-9-carboxylate

According to General NC Coupling Procedure 1, 3- (6-amino-pyridin-3-yl) -4-oxo-3,9- diaza- bicyclo [4.2.1] nonane-9- Butyl ester was combined with 2-chloro-7- [4- (cyano-dimethyl-methyl) -phenyl] -7H-pyrrolo [2,3- d] pyrimidine-6- carboxylic acid dimethylamide to give tert- Pyrrolo [2,3-d] pyrimidin-2-yl) -pyrrolidine The title compound was obtained as colorless crystals from 3- (6- (7- (4- (2-cyanopropan- Ylamino) pyridin-3-yl) -4-oxo-3,9-diazabicyclo [4.2.1] nonane-9-carboxylate (160 mg) in 89% yield.

Step 2

N, N-dimethyl-2- (5- (4-oxo-3,9-diazabicyclo [4.2.1] Yl) pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide.

According to the deprotection method 1, tert-butyl 3- (6- (7- (4- (2-cyanopropan-2-yl) phenyl) -6- (dimethylcarbamoyl) -7H- pyrrolo [ Yl) -4-oxo-3,9-diazabicyclo [4.2.1] nonane-9-carboxylate was reacted with 7- (4- (4-oxo-3,9-diazabicyclo [4.2.1] nonan-3-yl) pyridin-2 -Ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide (72 mg) in 53% yield.

Example 128

Pyridin-2-ylamino] -7-phenyl-7H-pyrrolo [2,3- 3-d] pyrimidine-6-carboxylic acid dimethylamide

Step 1

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridin-3-yl] -4-oxo-3, Diaza-bicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester.

Pyrrolidine 2,3-d] pyrimidine-6-carboxylic acid dimethylamide (181 mg, 0.602 mmol) was reacted with 3- (6-chloro- 3-yl) -4-oxo-3,9-diaza-bicyclo [4.2.1] nonane-9-carboxylic acid tert- butyl ester (200 mg, 0.602 mmol) Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridin-3-yl] -4-oxo-3,9- Diaza-bicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester (320 mg, 0.536 mmol) in 86% yield.

Step 2

Pyridin-2-ylamino] -7-phenyl-7H-pyrrolo [2,3- 3-d] pyrimidine-6-carboxylic acid dimethylamide.

Deprotection According to Method 1, 3- [6- (6-dimethylcarbamoyl-7-phenyl-7H-pyrrolo [2,3- d] pyrimidin- 2- ylamino) -pyridin- Carboxylic acid tert-butyl ester (320 mg, 0.536 mmol) was reacted with 2- [5- (4-oxo-3, Dihydro-9H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid Dimethylamide (200 mg, 0.403 mmol).

Step 3.

Pyridin-2-ylamino] -7-phenyl-7H-pyrrolo [2,3- 3-d] pyrimidine-6-carboxylic acid dimethylamide the enantiomers of chiral chromatography (AD-H column, 21x250 mm column, 0.2% diethylamine / 60% to 40% isopropyl alcohol containing CO ₂₎ To obtain the following.

Example 129

Synthesis of 2- [5 - ((1S, 6R) -4-oxo-3,9-diaza-bicyclo [4.2.1] non- - pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Example 130

Synthesis of 2- [5 - ((lR, 6S) -4-oxo-3,9-diaza-bicyclo [4.2.1] -Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Example 131

(4-oxo-3,9-diazabicyclo [4.2.1] nonan-3-yl) pyridin-2-ylamino) -7H-pyrrolo [ Lt; / RTI &gt; [2,3-d] pyrimidine-6-carboxamide

Step 1

pyridin-2-ylamino) pyridin-3-yl) -4H-pyrrolo [2,3- -Oxo-3,9-diazabicyclo [4.2.1] nonane-9-carboxylate.

Following general NC coupling procedure 1, tert-butyl 3- (6-aminopyridin-3-yl) -4-oxo-3,9-diazabicyclo [4.2.1] nonane-9- carboxylate pyrrolo [2,3-d] pyrimidine-6-carboxamide (111 mg, 0.361 mmol) was combined with tert-butyl N- Pyridin-2-ylamino) pyridin-3-yl) -4- (4-fluorophenyl) Oxazin-3,9-diazabicyclo [4.2.1] nonane-9-carboxylate (120 mg) in 55.1% yield.

Step 2

(4-oxo-3,9-diazabicyclo [4.2.1] nonan-3-yl) pyridin-2-ylamino) -7H-pyrrolo [ Lt; / RTI &gt; [2,3-d] pyrimidine-6-carboxamide.

Deprotection According to Method 1, tert-butyl 3- (6- (7-cyclohexyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3- d] pyrimidin- Diazabicyclo [4.2.1] nonane-9-carboxylate (120 mg, 0.199 mmol) was added to a solution of 7-cyclohexyl-N, N-dimethyl- Pyrrolo [2,3-d] pyrimidin-6-ylmethyl) -lH-pyrrolo [2,3-d] pyrimidin- Lt; / RTI &gt; hydrochloride salt of the carboxamide (90 mg) in 90% yield.

Example 132

Yl) -pyridin-2-ylamino] - (4-fluoropyridin-2-yl) 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

The enantiomers were separated by chiral chromatography (AD-H column, 21 x 250 mm column, 40% isopropyl alcohol containing 0.2% diethylamine / 60% CO ₂ ): Enantiomer 1 had a retention time of 1.75 min Respectively.

Example 133

4-oxo-3,9-diaza-bicyclo [4.2.1] non-3-yl) -pyridin- 2- ylamino] - 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Enantiomer 2 had a residence time of 2.21 min.

Example 134

Pyridin-2-ylamino] -7H-pyrrolo [2, 4-dihydro- , 3-d] pyrimidine-6-carboxylic acid dimethylamide

Step 1

pyrrolo [2,3-d] pyrimidin-2-ylamino) pyridin-3-yl) -4H-pyrazolo [3,4-d] pyrimidin- -Oxo-3,9-diazabicyclo [4.2.1] nonane-9-carboxylate

According to general NC coupling procedure 1 tert-butyl-3- (6-aminopyridin-3-yl) -4-oxo-3,9-diazabicyclo [4.2.1] nonane-9- carboxylate 119 mg, 0.359 mmol) was combined with 2-chloro-7-cyclobutyl-N, N-dimethyl-7H- pyrrolo [2,3- d] pyrimidine- 6- carboxamide (100 mg, 0.359 mmol) pyrrolo [2,3-d] pyrimidin-2-ylamino) pyridin-3-yl) -4H-pyrazolo [3,4-d] pyrimidin- -Oxo-3,9-diazabicyclo [4.2.1] nonane-9-carboxylate (150 mg) in 73% yield.

Step 2

Pyridin-2-ylamino] -7H-pyrrolo [2, 4-dihydro- , 3-d] pyrimidine-6-carboxylic acid dimethylamide

Deprotection According to Method 1, tert-butyl 3- (6- (7-cyclobutyl-6- (dimethylcarbamoyl) -7H-pyrrolo [2,3- d] pyrimidin- Yl) -4-oxo-3,9-diazabicyclo [4.2.1] nonane-9-carboxylate (153 mg, 0.266 mmol) Pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid Dimethylformamide &lt; / RTI &gt; (76 mg) in 60% yield.

Example 135

Yl) -pyridin-2-ylamino] - (4-fluorobenzyl) -2,3-dihydro- 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Using chiral chromatography (IA column, 21 x 250 mm column, 0.2% diethylamine / 40% isopropyl alcohol containing 60% CO ₂ ) 7-cyclobutyl-2- [5- (4- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide was prepared in accordance with the general method of example 1 from The enantiomers were separated.

Diastereomeric mixture of 1, 7-cyclobutyl-2- [5 - ((1S, 6R) -4-oxo- Ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide had a retention time of 1.98 min.

Example 136

Synthesis of 7-cyclobutyl-2- [5 - ((lR, 6S) -4-oxo-3,9-diaza-bicyclo [ 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Dihydro-isoquinolin-2-yl) -pyridin-2-yl] -pyridin-2- Ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide had a retention time of 2.72 min.

Example 137

Synthesis of 7-cyclopentyl-N, N-dimethyl-2- (5 - ((1S, 6R) -9- (methylsulfonyl) -4-oxo-3,9-diazabicyclo [4.2.1] Yl) pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide

Synthesis of 7-cyclopentyl-N, N-dimethyl-2- (5 - ((1S, 6R) -9- (methylsulfonyl) -4-oxo-3,9-diazabicyclo [4.2.1] Yl) pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide

Synthesis of 7-cyclopentyl-N, N-dimethyl-2- (5 - ((1S, 6R) -4-oxo-3,9-diazabicyclo [4.2.1] non- (50 mg, 0.102 mmol), methanesulfonyl chloride (12.3 mg, 0.107 mmol) and diisopropylethylamine (0.027 ml, , 0.154 mmol) was added to 1 ml DCM in a screw cap vial with stir bar and allowed to stir for 16 hours. The reaction was then dissolved in EtOAc, extracted with saturated Na ₂ CO ₃ solution, and the brine and organic layers were dried over Na ₂ SO ₄ . The crude product was purified by normal chromatography (0-75% ethyl acetate in heptane) to give 7-cyclopentyl-N, N-dimethyl-2- (5- (1S, 6R) -9- (methylsulfonyl) Pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide (25 mg) in 44% yield.

Example 138

Synthesis of 2- (5 - ((1S, 6R) -9- (2-acetamidoacetyl) -4-oxo-3,9-diazabicyclo [4.2.1] non- Amino) -7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide

Synthesis of 2- (5 - ((1S, 6R) -9- (2-acetamidoacetyl) -4-oxo-3,9-diazabicyclo [4.2.1] non- Amino) -7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide.

2-Acetamidoacetic acid (12 mg, 0.102 mmol) was combined with diisopropylethylamine (0.018 ml, 0.102 mmol) and HBTU (38.8 mg, 0.102 mmol) in DMF (15 ml) Then, a solution of 7-cyclopentyl-N, N-dimethyl-2- (5 - ((1S, 6R) -4-oxo-3,9-diazabicyclo [4.2.1] non- Pyrrolo [2,3-d] pyrimidine-6-carboxamide (50 mg, 0.102 mmol) was added and the reaction was allowed to stir for 4 hours. The reaction was then poured into brine and extracted with ethyl acetate. The combined ethyl acetate extracts were dried with sodium sulfate, filtered, concentrated and the resulting residue was purified by silica gel chromatography to give 2- (5 - ((1S, 6R) -9- (2- Pyridin-2-ylamino) -7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [ 3-d] pyrimidine-6-carboxamide (45 mg) was obtained in 77% yield.

Example 139

Synthesis of 2- (5 - ((1S, 6R) -9-acetyl-4-oxo-3,9-diazabicyclo [4.2.1] -N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide

Synthesis of 2- (5 - ((1S, 6R) -9-acetyl-4-oxo-3,9-diazabicyclo [4.2.1] -N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide.

Synthesis of 7-cyclopentyl-N, N-dimethyl-2- (5 - ((1S, 6R) -4-oxo-3,9-diazabicyclo [4.2.1] non- (50 mg, 0.102 mmol), acetic anhydride (0.020 ml, 0.113 mmol) and diisopropylethylamine (0.014 ml, 0.154 mmol) were added to a solution of 4- mmol) was combined with 1 ml DCM. Dissolve the mixture, and then, EtOAc to stir for 16 hours, washed with brine, dried over Na ₂ SO _4, filtered, and concentrated. The crude product was purified by silica gel chromatography to give 2- (5 - ((1S, 6R) -9-acetyl-4-oxo-3,9-diazabicyclo [4.2.1] Pyrimidin-6-carboxamide (32 mg) was obtained in 52% yield.

Example 140

Synthesis of 7-cyclopentyl-N, N-dimethyl-2- (5 - ((1R, 6S) -9- Ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide

Synthesis of 7-cyclopentyl-N, N-dimethyl-2- (5 - ((1R, 6S) -9- -2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide.

According to General Reduction Alkylation Method 1, 7-cyclopentyl-N, N-dimethyl-2- (5 - ((1R, 6S) -4-oxo-3,9-diazabicyclo [4.2.1] Pyrrolo [2,3-d] pyrimidine-6-carboxamide (90 mg, 0.184 mmol) was dissolved in formaldehyde (37% solution in water, 0.041 ml, 1.474 mmol), followed by silica gel chromatography to obtain 7-cyclopentyl-N, N-dimethyl-2- (5 - ((1R, 6S) -9-methyl-4-oxo-3,9-diazabicyclo [4.2 Yl] pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide (90 mg) in 97% yield.

Example 141

Synthesis of 7-cyclopentyl-2- [5 - ((1S, 6R) -9-methyl-4-oxo- Ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Synthesis of 7-cyclopentyl-2- [5 - ((1S, 6R) -9-methyl-4-oxo- Ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Synthesis of 7-cyclopentyl-2- [5 - ((1S, 6R) -4-oxo-3,9-diaza- bicyclo [4.2.1] non- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide was combined with formaldehyde (37% solution in water) to give 7-cyclopentyl-2 - [5 - ((1S, 6R) -9-methyl-4-oxo-3,9- diaza- bicyclo [ Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (41 mg) was obtained in 80% yield.

Example 142 [

Synthesis of 7-cyclopentyl-2- [5- ((1S, 6R) -9-isopropyl-4-oxo-3,9- diaza- bicyclo [4.2.1] non- -Ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Synthesis of 7-cyclopentyl-2- [5- ((1S, 6R) -9-isopropyl-4-oxo-3,9- diaza- bicyclo [4.2.1] non- -Ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

According to General Reduction Alkylation Method 1, 7-cyclopentyl-N, N-dimethyl-2- (5 - ((1S, 6R) -4-oxo-3,9-diazabicyclo [4.2.1] Pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide (65 mg, 0.133 mmol) was combined with acetone (0.05 mL, 0.665 mmol) Synthesis of cyclopentyl-2- [5 - ((1S, 6R) -9-isopropyl-4-oxo-3,9- diaza- bicyclo [4.2.1] non- Amino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (61 mg) in 86% yield.

Example 143

Synthesis of 7-cyclopentyl-2- [5 - ((1S, 6R) -9-tridecylmethyl-4-oxo-3,9-diazabicyclo [4.2.1] non- -Ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Synthesis of 7-cyclopentyl-2- [5 - ((1S, 6R) -9-tridecylmethyl-4-oxo-3,9-diazabicyclo [4.2.1] non- -Ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

According to General Reduction Alkylation Method 1, 7-cyclopentyl-N, N-dimethyl-2- (5 - ((1S, 6R) -4-oxo-3,9-diazabicyclo [4.2.1] (50 mg, 0.102 mmol) was added to formaldehyde-d ₂ (0.015 ml, 0.015 mL) and the mixture was stirred at -78 &lt; 0 & To give 7-cyclopentyl-2- [5 - ((lS, 6R) -9-tridecylmethyl-4-oxo-3,9-diazabicyclo [4.2.1] non- Ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (43 mg) was obtained in 85% yield.

Example 144

7-cyclopentyl-N, N-dimethyl-2- (5 - ((1R, 6S) -4-oxo-9- (2,2,2- trifluoroethyl) -3,9-diazabicyclo [ 4.2.1] nonan-3-yl) pyridin-2-ylamino) -7H-pyrrolo [2,3- d] pyrimidine-

7-cyclopentyl-N, N-dimethyl-2- (5 - ((1R, 6S) -4-oxo-9- (2,2,2- trifluoroethyl) -3,9-diazabicyclo [ 4.2.1] nonan-3-yl) pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine- 6- carboxamide.

Synthesis of 7-cyclopentyl-N, N-dimethyl-2- (5 - ((1S, 6R) -4-oxo-3,9-diazabicyclo [4.2.1] non- Amino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide (60 mg, 0.123 mmol) was added to a solution of 2,2,2-trifluoroethyl Trifluoromethanesulfonate (0.035 ml, 0.246 mmol) was combined and heated to 80 &lt; 0 &gt; C overnight. The reaction was then poured into water and extracted with ethyl acetate. The aqueous layer was washed with ethyl acetate. The organics were combined, dried over sodium sulfate, filtered and concentrated to give the crude material which was purified by silica gel column chromatography to give 7-cyclopentyl-N, N-dimethyl-2- (5- ( 6S) -4-oxo-9- (2,2,2-trifluoroethyl) -3,9-diazabicyclo [4.2.1] nonan-3- yl) pyridin- Pyrrolo [2,3-d] pyrimidine-6-carboxamide (45 mg) was obtained in 64% yield.

Example 145

Cyclopentyl-2- [5- (4-oxo-8-oxa-3,10-diaza-bicyclo [4.3.1] dec- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide

Step 1

Preparation of 3- (6-Nitro-pyridin-3-yl) -4-oxo-8-oxa-3,10-diaza- bicyclo [4.3.1] decane-10-carboxylic acid tert-butyl ester

Oxo-8-oxa-3,10-diaza-bicyclo [4.3.1] decane-10-carboxylic acid tert-butyl ester (0.776 g, 3.03 mmol) To a solution of 3- (6-nitro-pyridin-3-yl) -4-oxo-8-oxa-3,10-diaza- bicyclo [4.3.1] decane-10-carboxylic acid tert-butyl ester (0.69 g, 1.732) in 57.2 yield.

Step 2

Preparation of 3- (6-Amino-pyridin-3-yl) -4-oxo-8-oxa-3,10-diaza- bicyclo [4.3.1] decane-10-carboxylic acid tert-butyl ester

Following the general nitro reduction procedure, the title compound was obtained from 3- (6-nitro-pyridin-3-yl) -4-oxo-8-oxa-3,10-diaza- bicyclo [4.3.1] decane- butyl ester (690 mg, 1.824 mmol) was reacted with 3- (6-amino-pyridin-3-yl) -4-oxo-8-oxa-3,10- diaza- bicyclo [4.3.1] decane- 10-carboxylic acid tert-butyl ester (351 mg, 1.007 mmol) in 55.2% yield.

Step 3

Pyrrolo [2,3-d] pyrimidin-2-ylamino) -pyridin-3-yl] -4-oxo-8,8-dihydro- -Oxa-3,10-diaza-bicyclo [4.3.1] decane-10-carboxylic acid tert-butyl ester

According to general NC coupling procedure 1, 3- (6-amino-pyridin-3-yl) -4-oxo-8-oxa-3,10-diaza- bicyclo [4.3.1] decan- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide (350 mg, 1.151 mmol) Pyrimidin-2-ylamino) -pyridin-3-yl] -4- (4-methylpiperazin-1- Oxa-8-oxa-3,10-diaza-bicyclo [4.3.1] decane-10-carboxylic acid tert-butyl ester (476 mg, 0.787 mmol) in 75% yield.

Step 4

Cyclopentyl-2- [5- (4-oxo-8-oxa-3,10-diaza-bicyclo [4.3.1] dec- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

Deprotection According to Method 1, 3- [6- (7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo [2,3- d] pyrimidin- 2- ylamino) -pyridin- ] -4-oxo-8-oxa-3,10-diaza-bicyclo [4.3.1] decane-10-carboxylic acid tert- butyl ester (470 mg, 0.777 mmol) 2,3-dioxo-bicyclo [4.3.1] dec-3-yl) -pyridin- 2- ylamino] -7H-pyrrolo [2,3- d] pyrimidine-6-carboxylic acid dimethylamide (231 mg, 0.457 mmol) in 58.8% yield.

Examples 146-147

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- d] pyrimidine-6-carboxylic acid dimethylamide was separated by chiral separation (enantiomer 1) to give 7-cyclohexyl-2- [5 - ((S) -l-oxo-hexahydro- pyrrolo [ Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide and (enantiomer 2) 7-Cyclohexyl Pyridin-2-ylamino] -7H-pyrrolo [2,3-a] pyrimidin- / RTI &gt; d] pyrimidine-6-carboxylic acid dimethylamide.

Example 146

Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- [2,3-d] pyrimidine-6-carboxylic acid dimethylamide.

White solid (4 mg)

Example 147

Pyrrol-2-yl) -pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidin- [2,3-d] pyrimidine-6-carboxylic acid dimethylamide. The white solid (5 mg)

Biological assay

CDK4 / Cyclin D1 Enzyme Activity Assay

Assays for monitoring CDK4 / Cyclin D1-catalyzed phosphorylation of pRb at the Ser780 site were performed using TR-FRET in 384-well format and used for IC ₅₀ measurements and kinetic analysis. The reactions were incubated with 0.3 nM CDK4 / Cyclin D1, 150 nM biotin (50 mM HEPES-Na, pH 7.5; 5 mM MgCl ₂ , 1 mM DTT, 0.02% Tween- 20 and 0.05% BSA) pRb (773-924), 3 [mu] M ATP and 1.3% DMSO (or compound in DMSO). 3 μM ATP was added last to initiate the reaction. After incubation at 22 ° C for 60 minutes, the reaction was quenched with 10 μL of 240 mM EDTA-Na (pH 8.0). Signal was detected with 40 nM SA-APC in a detection buffer (50 mM HEPES-Na, pH 7.5, 60 mM EDTA-Na, pH 8.0, 0.05% BSA and 0.1% Triton X- -Phospho-pRb (S780) antibody and 1 nM Eu-W1024 anti-rabbit IgG antibody. After incubation in the dark room for 60 minutes, the plate was read on Envision (Perkin Elmer 2102-0010).

Human CDK4 / Cyclin D1 was expressed in Sf21 cells via baculovirus infection.

CDK6 / Cyclin D3 enzyme activity assays can be performed using the general procedure outlined in the CDK4 / Cyclin D1 enzyme assay. The CDK6 / Cyclin D3 enzyme complex is available from commercial sources (Carna Biosciences, catalog number 04-107).

CDK1 / Cyclin B enzyme activity assay

A 384-well microtiter IMAP-FP (TM) (Molecular Devices Trade Mark Technology) endpoint assay was used for CDK1 / Cyclin B kinase activity measurements. The same assay was used for IC ₅₀ determinations of small molecule inhibitors. Generally, the kinase reaction is carried out in a reaction buffer containing 1 μl of a solution containing 2 μL of compound (in 20% DMSO), 8 μL of CDK1 / Cyclin B in 1 × reaction buffer (Molecular Devices, catalog number R8139) In a reaction solution consisting of 10 μL of a substrate mixture of Tamra Histone-H1 peptide (Molecular Devices, catalog number R7384) and ATP (Amersham Pharmacia, catalog number 27-2056-01) Respectively. The final reaction mixture contained compound (inhibitor) with various concentrations of 0.005-10 μM, 2% DMSO, 0.25 nM CDK1 / Cyclin B, 100 nM Tamra histone-H1 peptide and 20 μM ATP.

All reactions were performed in black 384-well flat-bottom Costar plates (Corning, Cat. No. 3710) for 120 minutes at room temperature and then diluted 1: 400 dilution of 1x Gradual Binding Buffer A (Molecular Devices, Catalog number < RTI ID = 0.0 > R8139). &Lt; / RTI &gt; The fluorescence polarization signal was read on an Enbine multi-label reader (PerkinElmer, Envie 2102-0010) after incubation for 2 hours at room temperature. Note: IC ₅₀ <0.005 nM or IC ₅₀ > 10 μM indicates that the actual IC ₅₀ is out of detection range.

CDK4 cell assay

Cell-based assays to measure phosphorylation levels of pRb at the Ser780 site using an enzyme-linked immunosorbent assay (ELISA) method (Table 6). The covert-cell lymphoma cell line, JeKo-1, was selected for use in this assay due to its known disposition and subsequent overexpression of cyclin D1. [Amin, H. M .; McDonnell, T. J .; Medeiros, L.J .; Rassidakis, G. Z .; Leventaki, V .; O'Connor, S. L .; Keating, M. J .; Lai, R. Characterization of four mantle cell lymphoma cell lines - Establishment of an in vitro study model. Arch. Pathol. Lab. Med. 2003, 127, 424-431].

pRb expressing JeKo-1 coat cell lymphoma cell line was cultured in RPMI1640 (Gibco catalog number 22400-071), 20% FBS (Gibco catalog number 10082-131), 2 mM L-glutamine (Gibco catalog number 25030-081) % Penicillin / streptomycin (Gibco cat. # 15140-133). JeKo-1 cells were seeded at 20,000 cells / well in complete medium of 100 μL final volume in Biocoat cell culture poly-D-lysine 96-well tissue culture plates (Becton Dickinson cat. No. 356461) . Cells were allowed to attach overnight. Compounds were prepared as 10 mM stocks in DMSO and diluted to a concentration of 110 μM in complete medium on 96-well tissue culture plates and then serially diluted four times to yield titration curves at 7 sites with a final concentration of 26 nM . Then, 10 μL of the dilution was transferred to a cell culture plate to produce a final concentration range of 10 μM to 2 nM. The incubation was performed at 37 ℃ with 5% CO _2. All compounds were tested in triplicate at each concentration. Following compound incubation, the medium was removed and cells were resuspended in 50 mM Tris.Cl, pH 7.2, 120 mM NaCl, 1 mM EDTA, 6 mM EGTA, 1% NP-40, complete protease inhibitor cocktail (Roche, No. 11836170001) and a protease inhibitor cocktail (catalog number 524525) from Calbiochem (catalog number 524525). The plates were kept at 4 [deg.] C with vigorous shaking for 5 minutes to lyse the cells. The resulting lysate contained approximately 1 μg / μL of protein.

The 4H1 total pRb antibody (catalog number 9309) from Cell signaling technology was transferred to a clear MaxiSorp plate (Nunc catalog number 442404) at a concentration of 50 ng per well using Dulbecco's phosphate buffered saline (DPBS) (Gibco catalog number 14190-144). The plates were incubated overnight at 4 [deg.] C with shaking. After washing 250 μL with TBST (Teknova Cat. No. T9501) and drying the blots, 250 μL of Superblock (Pierce Cat. No. 37535) was added to each well. After shaking for 10 minutes, the superblock solution was replaced with a new superblock, and the plate was incubated on the shaker for an additional 50 minutes. After blocking, 30 μL of JeKo-1 cell lysate containing approximately 10 μg total protein was added to the wells in triplicate. 20 [mu] L of PBS (Gibco cat # 10010-023) containing 10% superblock (Pierce catalog number 37535) was added to each well in a final reaction volume of 50 [mu] L. The plate was then sealed with a Uniseal plate sealer (Whatman catalog number 7704-0007) and incubated on the shaker for 2 hours at room temperature. Plates were washed with 3 x 250 L TBST. 50 μL of a 1: 1000 dilution of anti-phosphoRb Ser ⁷⁸⁰ (catalog number 9307) from cell signaling in PBS / 10% Superblock was added and the plate was incubated on a shaker for 1 hour at room temperature. For all incubation steps, the plate was covered with a unicil plate sealer. Following incubation, the plates were washed with 3 x 250 L TBST. Next, 50 μL of a 1: 2500 dilution of donkey-anti-rabbit HRP (Promega Cat # W401B) in PBS / 10% superblock was added and the plate was incubated at room temperature for 30 minutes on a shaker . Plates were washed again as described above. Finally, 50 μL of Ultra TMB ELISA (Pierce Cat. No. 34028) was added, the plate incubated, opened and placed in the dark room for 5-15 minutes until the blue color developed. After incubation, 50 μL of 2 M sulfuric acid was added to the top of the reactants on the plate and the absorbance was measured at 450 nm within 15 minutes on SpectraMax (Molecular Devices, Sunnyvale, CA). All washing was carried out using a Bio-Tek plate washer.

A total Rb ELISA kit (Invitrogen catalog number KHO0011) was used to determine the level of total pRb. The kit uses a well precoated with an exclusive total pRb antibody for capture. All reagents listed were included in the kit, with the exception of cell lysates. The nature of the antibody used for capture and detection has been labeled as proprietary and has not been disclosed. 10 μg of cell lysate was loaded into the wells and the volume was adjusted to 50 μL using standard dilution buffer. The plate was sealed with the film included in the kit and incubated on the shaker for 2 hours at room temperature. The plate was then manually washed three times with 250 [mu] L of wash buffer. 50 μL of monoclonal primary antibody (pre-conjugated to biotin) was added to the wells and incubated on the shaker for 1 hour at room temperature. The plates were then washed again as mentioned above. Secondary antibody (HRP, pre-conjugated to streptavidin) was diluted 1: 100 in streptavidin-HRP dilution buffer and 50 μL was added to each well. The plate was then incubated for 30 minutes. The plate was then washed four times with buffer as outlined above. Finally, the stabilized chromogenic material was added in an amount of 50 μL per well, and the plate was incubated for 15 minutes, at which time 50 μL of the stop solution was added. Plates were then read at 450 nm on a spectra max.

Upon quantification of the level of pRb phosphorylation (p-pRb), the percent inhibition is derived from each concentration tested and is used to determine the 50% inhibitory concentration (IC ₅₀ ) (non-normalized) for a particular compound . Then, the total by adjusting the% inhibition value p-pRb with the pRb level describes any loss of the signal due to the absence of pRb protein itself, IC ₅₀ values obtained from the adjusted inhibition% is the normalized cell p-pRb IC ₅₀ .

Automated electrophysiology studies (Q-patch clamp black)

Cell culture: CHO cells constitutively expressing functional hERG channels were purchased from AVIVA Biosciences Corp. (San Diego, Calif.). Cells were cultured in DMEM / F12 (Gibco) supplemented with 10% FBS (Gibco Cat # 10082-142), 1% penicillin-streptomycin (Gibco Cat # 15140-122) and 1% Cat # 11039-021). Cells were separated by sucking media from the cultures when they reached a full culture rate of approximately 70-90%, and rinsing the cell monolayer with Dulbecco's PBS (Gibco Cat # 14190-136). After rinsing buffer was removed, trypsin / EDTA (0.05%, Gibco Cat # 25300-054) was added to cover the cell monolayer and incubated for 1 minute at room temperature. Trypsin / EDTA was withdrawn and the cells were allowed to stand for another minute. The flask was gently patted to allow cells to leave the flask. The complete medium was added and the cells were mixed and dissociated until the cells were separated by pipetting up and down several times. Cells were counted and cells were reseeded in the flask at 37 ° C., 5.0% CO ₂ , 100% humidity incubator in the case of cell passage, and at 30 ° C., 5.0% CO ₂ , 100% humidity in the case of compound screening. Before Q-patch assay, the growth medium was removed from the culture flask and the cells gently rinsed with 12 ml of D-PBS. The cells were immersed in trypsin / EDTA (freshly prepared from a 10x frozen stock solution containing D-PBS) at room temperature for approximately 30 seconds, then the solution was drawn and incubated at 37 DEG C for 3-4 minutes. At the end of the incubation, noticeably circular cells were easily dropped from the bottom of the flask without light knocking. Q patch-modified storage medium (CHO-S-SFM II, 25 mM HEPES and 0.04 mg / ml soybean trypsin inhibitor) was added and the cells were resuspended gently by pipetting up and down 6-10 times. Cell density and survival were measured with Beckman Vicell. The cell density was adjusted to 2-3 x 10 &lt; ⁶ &gt; / ml in the Q patch modified storage medium. The cell suspension was immediately applied to a storage vessel on a Q-patch platform.

Solutions and Drugs: Cells are centrifuged (150 g, 2 min), supernatant removed, cell pellet washed twice and finally re-expressed in extracellular solution (Na-Linger) containing was suspended (adjusted to pH 7.4) 145 NaCl, 4 KCl , 2 CaCl 2, 1 MgCl 2, 10 HEPES. An aliquot (300 ul) of the suspension (3-10 x 10 ⁶ cells / ml) was transferred to the chip. The intracellular solution consisted of the following (in mM): 120 KCl, 5.374 CaCl ₂ , 1.75 MgCl ₂ , 10 KOH / EGTA, 10 HEPES, 5 K ₂ -ATP (adjusted to pH 7.2). Amitriptyline (reference control) was from Sigma. All compounds were prepared at 10 mM in 100% DMSO. Each concentration was generated in triplicate in 96-well plates by 5-fold serial dilutions in 100% DMSO. Each dilution was then transferred to a 96-well glass-coated plate and an additional 333 fold (test concentration: 0.2 to 30 [mu] M) was added to the extracellular solution. The final DMSO concentration was? 0.3%.

Electrophysiology: All electrophysiological experiments were performed on a single-channel Q patch test version. The Q-plate has 16 recording chambers, each chamber having a patch clamp amplifier operating simultaneously. The amplifier is controlled by a custom-made digital signal processor (DSP) board by Sophion. In the hERG assay, the acquisition rate of the total-cell current during the voltage protocol run was 10 kHz. The current signal was digitally filtered (Bessel filter, order = 4) at a cut-off frequency of 3 kHz. CHO-hERG cells were maintained at-80 mV resting membrane potential for 100 msec, maintained at -50 mV for 100 msec (runoff subtraction), depolarized (+20 mV) for 4 sec After repolarization (test pulse) to -50 mV for a second, the retention potential was returned to -80 mV. The protocol was repeated every 20 seconds. Approximately 10 voltage protocols were performed during each baseline and increased dose application period.

Fluid engineering: A 5 to 15 μl volume of cell suspension, compound sample and Na-Linger (wash) were pipetted onto the chip.

Data analysis: The IC ₅₀ and heel coefficients were estimated as experimental dose-response data at optimal fit by the Hill equation:

The residual current (%) = maximum I + ((minimum I - maximum I) / (1+ (concentration / IC ₅₀ )

The fitting procedure returned values for two variable parameters: the IC ₅₀ value and the Hill slope.

Certain embodiments of the present invention were evaluated with a Q-patch clamp assay.

Biological data

The results of CDK4 and CDK1 enzyme activity assays and CDK4 cell assays are given in Table 1.

<Table 1>

Claims (24)

A compound according to formula (I):
(I)

In this formula,
R ¹ is C _3-7 alkyl; C _4-7 cycloalkyl substituted or unsubstituted with one substituent selected from the group consisting of C _1-6 alkyl and OH; Phenyl substituted with one substituent selected from the group consisting of C _1-6 alkyl, C (CH ₃ ) ₂ CN and OH; Piperidinyl substituted or unsubstituted with one cyclopropyl or C _1-6 alkyl; Tetrahydropyranyl substituted with one cyclopropyl or C _1-6 alkyl; Or bicyclo [2.2.1] heptanyl;
A is CH or N;
R ¹¹ is hydrogen or C _1-4 alkyl;
L is a bond or C (O);
R ^2Y is

ego;
V is NH or CH ₂ ;
X is O or CH ₂ ;
W is O or NH;
m and n are each independently 1, 2 or 3, provided that m and n are not both 3;
Each R ^2Y is hydroxy, NH ₂ and substituted -SC from the group consisting of _{1 to 3} alkyl each with 1 or 2 substituents selected independently or unsubstituted C _1-3 alkyl; CD ₃ ; Halo; Oxo; C _1-3 haloalkyl; Hydroxy; NH ₂ ; Dimethylamino; benzyl; -C (O) -C _1-3 alkyl substituted or unsubstituted with one or two substituents each independently selected from the group consisting of NH ₂ , -SCH ₃ and NHC (O) CH ₃ ; -S (O) _2- C _1-4 alkyl; Pyrrolidinyl-C (O) -; And -C (O) _2- C _1-3 alkyl, each of which is unsubstituted or substituted with 1 to 4 substituents each independently selected from the group consisting of -C (O) ₂ -C _1-3 alkyl;
R ⁴ is hydrogen, deuterium or C (R ⁵ ) (R ⁶ ) (R ⁷ );
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently H or deuterium. 2. The compound of claim 1, wherein R < 1 >
(IB)

In this formula,
L is a bond or C (O);
R ^2Y is

ego;
V is NH or CH ₂ ;
X is O or CH ₂ ;
W is O or NH;
m and n are each independently 1, 2 or 3, provided that m and n are not both 3;
Each R ^2Y is hydroxy, NH ₂ and substituted -SC from the group consisting of _{1 to 3} alkyl each with 1 or 2 substituents selected independently or unsubstituted C _1-3 alkyl; CD ₃ ; C _1-3 haloalkyl; Hydroxy; NH ₂ ; Dimethylamino; benzyl; -C (O) -C _1-3 alkyl substituted or unsubstituted with one or two substituents each independently selected from the group consisting of NH ₂ , -SCH ₃ and NHC (O) CH ₃ ; -S (O) _2- C _1-4 alkyl; Pyrrolidinyl-C (O) -; And -C (O) ₂ -C _1-3 alkyl, each of which is unsubstituted or substituted with one to four substituents each independently selected from the group consisting of-C (O) ₂ -C _1-3 alkyl. 3. The compound according to claim 1 or 2, wherein L is C (O), or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1 or 2, wherein L is a bond, or a pharmaceutically acceptable salt thereof. 10. The compound of claim 1, wherein A is CH and R &lt; ¹¹ &gt; is hydrogen, or a pharmaceutically acceptable salt thereof. The compound according to claim 1, wherein R ⁴ is C (R ⁵ ) (R ⁶ ) (R ⁷ ) and R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are hydrogen, Salt. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ is C _4-7 cycloalkyl substituted or unsubstituted with one C _1-6 alkyl. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ is cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. 2. The compound according to claim 1, wherein R &lt; ^{1 &gt;} is unsubstituted cyclopentyl or a pharmaceutically acceptable salt thereof. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ^2Y is unsubstituted. The method of claim 1 wherein, R ^2Y is unsubstituted or substituted by one C _1-3 alkyl

Or a pharmaceutically acceptable salt thereof. The method according to claim 1,
Cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-aza- lt; / RTI &gt; d] pyrimidine-6-carboxamide;
(3, 8-diaza-bicyclo [3.2.1] octane-3-carbonyl) -pyridin-2- ylamino] -7H- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide;
Synthesis of 7-cyclopentyl-2- [5- (4-oxo-3,9-diaza-bicyclo [4.2.1] non-3-yl) -pyridin- 2-ylamino] -7H- pyrrolo [ , 3-d] pyrimidine-6-carboxylic acid dimethylamide;
Synthesis of 7-cyclopentyl-2- [5- ((lR, 6S) -4-oxo-3,9-diaza-bicyclo [4.2.1] 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide;
2-ylamino] -7H-pyrrolo [2,3-c] pyridin-2- d] pyrimidine-6-carboxylic acid dimethylamide;
Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- d] pyrimidine-6-carboxylic acid dimethylamide;
2-ylamino] -7H-pyrrolo [2,3-c] pyridin-2- d] pyrimidine-6-carboxylic acid dimethylamide;
Pyridin-2-ylamino) -7-cycloheptyl-N, N-dimethyl-7H-pyrrolo [2,3 lt; / RTI &gt; d] pyrimidine-6-carboxamide;
Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- 2,3-d] pyrimidine-6-carboxylic acid dimethylamide;
Synthesis of 7-cyclopentyl-2- [5 - ((S, S) -2,5-diaza-bicyclo [2.2.1] heptane- 2- carbonyl) -pyridin- Lt; / RTI &gt; [2,3-d] pyrimidine-6-carboxylic acid methylamide;
3-carbonyl) -pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidin- Pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide;
Diazabicyclo [3.3.1] nonane-9-carbonyl) pyridin-2-ylamino) -7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide;
2- [5- (3,8-diaza-bicyclo [3.2.1] octane-8-carbonyl) -pyridin-2-yl Amino] -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide;
Synthesis of 7-cyclopentyl-2- [5 - ((1S, 6R) -3,9-diaza-bicyclo [4.2.1] Lt; / RTI &gt; [2,3-d] pyrimidine-6-carboxylic acid dimethylamide;
Synthesis of 7-cyclopentyl-2- [5 - ((1R, 6S) -3,9-diaza-bicyclo [4.2.1] Lt; / RTI &gt; [2,3-d] pyrimidine-6-carboxylic acid dimethylamide;
2-ylamino] -7H-pyrrolo [2,3-c] pyridin-2- d] pyrimidine-6-carboxylic acid dimethylamide;
Pyrrolo [2,3-d] pyrimidin-2-yl] -pyridin- Pyrimidine-6-carboxylic acid dimethylamide;
Cyclopentyl-N, N-dimethyl-2- (5- (5'-oxo-8-azaspiro [bicyclo [3.2.1] octane-3,3'-pyrrolidin] ) Pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6- carboxamide;
Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- lt; / RTI &gt; d] pyrimidine-6-carboxylic acid dimethylamide;
Synthesis of 7-cyclopentyl-N, N-dimethyl-2- (5- (2-oxo-1-oxa-3,8-diazaspiro [4.5] decan- -Pyrrolo [2,3-d] pyrimidine-6-carboxamide;
Synthesis of 7-cyclopentyl-2- [5 - ((lS, 6R) -4-oxo-3,9-diaza-bicyclo [ 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide;
Pyridin-2-ylamino] -7-phenyl-7H-pyrrolo [2,3- 3-d] pyrimidine-6-carboxylic acid dimethylamide; And
(4-oxo-3,9-diazabicyclo [4.2.1] nonan-3-yl) pyridin-2-ylamino) -7H-pyrrolo [ Lt; / RTI &gt; [2,3-d] pyrimidine-6-carboxamide
&Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof. The method according to claim 1,
2-ylamino] -7H-pyrrolo [2,3-c] pyridin-2- d] pyrimidine-6-carboxylic acid dimethylamide;
Synthesis of 7-cyclopentyl-2- [5 - ((S, S) -2,5-diaza-bicyclo [2.2.1] heptane- 2- carbonyl) -pyridin- Lt; / RTI &gt; [2,3-d] pyrimidine-6-carboxylic acid dimethylamide;
Synthesis of 7-cyclopentyl-2- [5- ((lR, 6S) -4-oxo-3,9-diaza-bicyclo [4.2.1] 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide;
Synthesis of 7-cyclopentyl-2- [5 - ((1S, 5S) -3,6-diaza-bicyclo [3.2.1] octane- 3-carbonyl) -pyridin- Lt; / RTI &gt; [2,3-d] pyrimidine-6-carboxylic acid dimethylamide;
Yl) -pyridin-2-ylamino] - (4-fluorobenzyl) -2,3-dihydro- 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide;
4-oxo-3,9-diaza-bicyclo [4.2.1] non-3-yl) -pyridin- 2- ylamino] - 7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide;
Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- 2,3-d] pyrimidine-6-carboxylic acid dimethylamide;
Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- 2,3-d] pyrimidine-6-carboxylic acid dimethylamide;
Pyridin-2-ylamino] -7H-pyrrolo [2,3-c] pyridin- d] pyrimidine-6-carboxylic acid dimethylamide;
Synthesis of 7-cyclopentyl-N, N-dimethyl-2- (5- (3-oxo-1,4-diazabicyclo [3.2.2] Lt; / RTI &gt; [2,3-d] pyrimidine-6-carboxamide; And
Synthesis of 7-cyclopentyl-N, N-dimethyl-2- (5 - ((1R, 6S) -9- Ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide
&Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for use in the treatment of breast cancer, comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 7. The compound of claim 1 which is 7-cyclopentyl-N, N-dimethyl-2- (5 - ((1R, 6S) -9-methyl-4-oxo-3, 9-diazabicyclo [4.2 Yl] pyridin-2-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-6-carboxamide or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition for use in the treatment of breast cancer, comprising a compound according to claim 15 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 7. The compound of claim 1 which is 7-cyclopentyl-2- [5 - ((1R, 6S) -4-oxo-3,9- diaza- bicyclo [4.2.1] ) -Pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidine- 6- carboxylic acid dimethylamide or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 which is 7-cyclopentyl-2- [5 - ((1R, 6S) -4-oxo-3,9- diaza- bicyclo [4.2.1] ) -Pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid methylamide or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 which is 7-cyclopentyl-2- [5 - ((1R, 6S) -9-methyl-4-oxo-3,9- diaza- bicyclo [4.2.1] Yl) -pyridin-2-ylamino] -7H-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid methylamide or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 which is 7-cyclopentyl-2- [5- (3,8-diaza-bicyclo [3.2.1] octane-3-carbonyl) -pyridin- -7H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid dimethylamide, or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition for use in the treatment of breast cancer, comprising a compound according to claim 20 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. delete delete delete